INDRA statements for HCN4

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phosphosite cbn pc11 biopax bel_lc signor biogrid lincs_drug tas hprd trrust ctd virhostnet phosphoelm drugbank omnipath | geneways tees isi trips rlimsp medscan sparser eidos reach
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3',5'-cyclic AMP affects HCN4
| 1 29
3',5'-cyclic AMP activates HCN4.
| 1 17
3',5'-cyclic AMP activates HCN4. 17 / 17
| 1 17
reach
"HCN4 channels constitutively activated by basal intracellular cAMP production in bladder may serve as an effective therapeutic target for disorders affecting detrusor contractility such as OAB without any cardiac effects."
26709376
reach
"Intracellular cAMP positively modulates the gating of the HCN2 and HCN4 isoforms resulting in a shift of the activation curve by 15-20 mV in the positive direction."
25580535
reach
"The mHCN2-h4 channel reproduced key features of cAMP modulation of HCN4 channels."
23217679
reach
"Cyclic AMP (cAMP) enhances the activity of HCN2 and HCN4 isoforms by shifting the voltage dependence of activation to more depolarized potentials, whereas HCN1 and HCN3 isoforms are practically insensitive to this ligand."
29980633
reach
"The effect of adenosine on HCN cation current I h seems to involve the activation of adenylyl cyclase and the increase in intracellular cAMP that in turn activates HCN4 containing non selective cation channels that mediate I h."
29311923
reach
"Intracellular cAMP promotes activation of the HCN4 and HCN2 isoforms, while HCN1 and HCN3 are relatively insensitive to cAMP."
31290157
reach
"Alternatively, since HCN4 currents are modulated by cAMP [XREF_BIBR], activators of stimulatory and inhibitory G-proteins could affect HCN4 inward currents and regulate sour taste cell activation [XREF_BIBR, XREF_BIBR]."
19284629
reach
"Coassembly of PEX5R and Trip8b affects HCN channel gating in a subtype dependent and mode specific way : activation of HCN2 and HCN4 by cAMP is largely impaired, while gating by phosphoinositides and basal voltage-dependence remain unaffected."
19555650
reach
"Whereas the cAMP sensitivity of HCN1 and HCN3 is low, HCN2 and HCN4 are strongly modulated by cAMP [XREF_BIBR]."
22694806
reach
"Cyclic AMP (cAMP) enhances the activity of HCN2 and HCN4 isoforms by shifting the voltage dependence of activation to more depolarized potentials, whereas HCN1 and HCN3 isoforms are practically insensitive to this ligand."
29980633
reach
"For instance, it has been shown that in Chinese hamster ovary (CHO) cells external application of cAMP did not increase HCN4 channel activity in both whole-cell recordings and excised patches as the basal voltage dependence was already shifted to more depolarized potentials [XREF_BIBR]."
28950029
reach
"Although HCN4 channels are activated by cAMP, the sympathetic response of the SAN was preserved in patients carrying loss-of-function mutations of the HCN4 gene."
29315578
reach
"To address this possibility, we first confirmed that cAMP can bind to the isolated CNBD of HCN4 (as suggested by the elimination of cAMP modulation of HCN4 in HEK cells by the R669Q mutation; XREF_FIG)."
23109717
reach
"The cAMP dependent activation of HCN4 channels appeared to enhance this protective effect, rather than expediting sympathetic response of the SAN."
29315578
reach
"CAMP potentiates voltage dependent gating of HCN4 channels either by binding directly to a conserved cyclic nucleotide binding domain in the proximal C-terminus [XREF_BIBR, XREF_BIBR] or by protein kinase A (PKA)-mediated phosphorylation of the distal C-terminus [XREF_BIBR]."
28868308
reach
"Of the four different isoforms of HCN channels found in vertebrates (HCN1-4), HCN2 and HCN4 are strongly stimulated by cAMP, in contrast to HCN1 and HCN3."
29980633
reach
"Here, we utilize comparative S672R versus WT NMR analyses to show that the S672R mutation results in extensive perturbations of the dynamics in both apo- and holo-forms of the HCN4 isoform, reflecting how S672R remodels the free energy landscape for the modulation of HCN4 by cAMP, i.e. the primary cyclic nucleotide modulator of HCN channels."
28174302
3',5'-cyclic AMP binds HCN4.
| 10
3',5'-cyclic AMP binds HCN4. 10 / 10
| 10
reach
"Sympathetic stimulation increases cAMP in SAMs, and binding of cAMP to HCN4 channels shifts pore opening to more depolarized membrane potentials and slows channel closing."
31756134
reach
"Sympathetic stimulation increases cAMP in SAMs, and binding of cAMP to HCN4 channels shifts pore opening to more depolarized membrane potentials and slows channel closing."
31756134
reach
"In contrast to knockout of RyR2, NCX or CaMKII function, or Ankyrin-B, or mutations in human RyRs, genetic manipulation in mice including HCN2 or HCN4 (general or cardiac specific SA node and AV node) knock outs, or inhibition of cAMP binding to HCN4 subunits, have minimal or no effects on resting heart rate, or on increases in heart rate during exercise, or chronotropic effect of beta-AR stimulation (XREF_SUPPLEMENTARY)."
20203315
reach
"The study by Xu et al. first examined steady-state binding of cAMP to an isolated HCN4 C-linker-CNBD fragment (called CL-CNBD) by using two different equilibrium binding assays, isothermal titration calorimetry and fluorescence anisotropy."
23217679
reach
"Mice with a homozygous mutation of a single amino-acid exchange (R669Q) that prevented binding of cAMP to HCN4 channels, HCN4 R669Q and R669Q mice, are also embryonic lethal [XREF_BIBR]."
19573534
reach
"42 Similar observations were made in adult heterozygous knock-in mice expressing a cAMP binding deficient HCN4 subunit."
21499520
reach
"We studied the role of I (f) in mice, in which binding of cAMP to HCN4 channels was abolished by a single amino-acid exchange (R669Q)."
18219271
reach
"This depolarizing shift in voltage dependence appeared to result from direct binding of cAMP to HCN4 because it was eliminated by a point mutation (R669Q) at a conserved arginine in the CNBD that has been shown to disrupt cAMP binding to HCN4 and other cyclic nucleotide sensitive ion channels."
23109717
reach
"While cAMP binding to HCN4 modulates I f activation (XREF_FIG), studies in which either HCN2 or HCN4 channel were genetically modified in mice, and prior studies in which I f current was blocked in numerous species by ionic or pharmacological maneuvers, do not indicate that I f is required for the SANC basal beating rate, or for its modulation by beta-AR stimulation."
20156611
reach
"I (f) is produced by hyperpolarization activated cyclic nucleotide sensitive-4 (HCN4) channels, and it is widely believed that sympathetic regulation of I (f) occurs via direct binding of cAMP to HCN4, independent of phosphorylation."
21150293
3',5'-cyclic AMP inhibits HCN4.
| 2
3',5'-cyclic AMP inhibits HCN4. 2 / 2
| 2
reach
"In HCN4 channels, association with PEX5R antagonized the modulation of channel gating by cAMP very similar in extent to what was observed in HCN2 (values for DeltaV 1/2 by cAMP of 17.6 +/- 1.9 mV [n = 7] and 10.6 +/- 3.0 mV [n = 12] for HCN4 and HCN4+ PEX5R channels respectively, p < 0.001, Student 's t test; Figure 5 B)."
19555650
reach
"While rodent TC neurons are dominated by strongly cAMP modulated HCN2 and HCN4 channels XREF_BIBR XREF_BIBR, IN revealed at strong mRNA expression of the cAMP inhibited HCN3 isoform XREF_BIBR and the thalamic isoform HCN4 XREF_BIBR, thereby potentially explaining the reduced cAMP-sensitivity of IN."
27121468
PKA affects HCN4
| 12 11
PKA phosphorylates HCN4.
| 12 8
PKA phosphorylates HCN4. 20 / 20
| 12 8
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"cAMP potentiates voltage dependent activation of I f either by binding directly to HCN4 channels or by protein kinase A (PKA)-mediated phosphorylation of HCN4 channels."
28057842
reach
"Densitometric analysis was used to quantitate the PKA dependent phosphorylation of HCN4."
20713547
sparser
"cAMP potentiates voltage-dependent activation of I f either by binding directly to HCN4 channels ( xref ; xref ) or by protein kinase A (PKA)–mediated phosphorylation of HCN4 channels ( xref )."
28057842
reach
"This correspondence makes these positions particularly strong candidates for further analysis of PKA phosphorylation of HCN4 channels in vivo."
20713547
sparser
"The in vitro phosphorylation data demonstrated that PKA can directly phosphorylate HCN4 at multiple sites."
20713547
sparser
"This correspondence makes these positions particularly strong candidates for further analysis of PKA phosphorylation of HCN4 channels in vivo."
20713547
sparser
"PKA could directly phosphorylate HCN4 and, thus, regulate ion current changes [ xref ]."
27069490
reach
"PKA could directly phosphorylate HCN4 and, thus, regulate ion current changes [XREF_BIBR]."
27069490
sparser
"Densitometric analysis was used to quantitate the PKA-dependent phosphorylation of HCN4."
20713547
reach
"To determine whether PKA can directly phosphorylate HCN4, we next performed in vitro phosphorylation assays."
20713547
sparser
"At least 13 residues were identified in the intracellular N and C termini of HCN4 that can be phosphorylated by PKA in vitro ."
27069490
reach
"However, we have recently shown that Protein Kinase A (PKA) activity is required for sympathetic regulation of I (f) and that PKA can directly phosphorylate HCN4."
21150293
sparser
"PKA phosphorylates multiple sites on HCN4."
20713547
sparser
"In vitro phosphorylation assays and mass spectrometry revealed that PKA can directly phosphorylate at least 13 sites on HCN4, including at least three residues in the N terminus and at least 10 in the C terminus."
20713547
reach
"From these studies, it seems clear that PKA can phosphorylate HCN4 and that PKA phosphorylation alters the voltage dependence of HCN4 activation."
20713549
sparser
"However, we have recently shown that Protein Kinase A (PKA) activity is required for sympathetic regulation of I(f) and that PKA can directly phosphorylate HCN4."
21150293
sparser
"From these studies, it seems clear that PKA can phosphorylate HCN4 and that PKA phosphorylation alters the voltage dependence of HCN4 activation."
20713549
reach
"The in vitro phosphorylation data demonstrated that PKA can directly phosphorylate HCN4 at multiple sites."
20713547
sparser
"To determine whether PKA can directly phosphorylate HCN4, we next performed in vitro phosphorylation assays."
20713547
sparser
"We identified at least 13 residues in the intracellular N and C termini of HCN4 that can be phosphorylated by PKA in vitro."
20713547
PKA activates HCN4.
| 3
PKA activates HCN4. 3 / 3
| 3
reach
"By a deletion and mutagenesis strategy, they could pinpoint a region in the distal C terminus containing four PKA sites that was necessary for the PKA modulation of HCN4 channels (XREF_FIG)."
20713549
reach
"HCN4 is the predominant cAMP gated channel for I f in SANC 32 and new studies show that HCN4 is also activated by PKA phosphorylation."
21406683
reach
"These four alanine substitutions eliminated the ability of PKA to shift the voltage dependence of HCN4-Cx4 channels (V 1/2 = -105.0 +/- 3.7 mV, n = 8 in control, -107.5 +/- 1.7 mV, n = 6 in PKA; XREF_FIG and XREF_FIG), indicating that this regulatory site is obligatory for modulation of HCN4 by PKA."
20713547
CAV3 affects HCN4
| 5 8 10
CAV3 binds HCN4.
| 5 8 2
CAV3 binds HCN4. 10 / 10
| 5 8 2
sparser
"The immunoprecipitation results indicated an association of HCN4 and Cav3 in the heart and in HEK293 cells."
19238754
reach
"Molecular and functional evidence of HCN4 and caveolin-3 interaction during cardiomyocyte differentiation from human embryonic stem cells."
23311301
sparser
"These results confirm that the HCN4 and Cav3 proteins may be associated with one another."
19238754
sparser
"Interestingly, studies have shown that Cav3 is associated with HCN4, and affects its function [ xref ]."
27807743
sparser
"We sought to determine whether HCN4 associates with Cav3 in the heart."
19238754
sparser
"We conclude that HCN4 associates with Cav3 to form a HCN4 macromolecular complex."
19238754
sparser
"A number of laboratories including ours have provided evidence that HCN4 channels are localized to caveolae based on the presence of HCN4 in low density membrane fractions along with Cav-3 as well as the specific interaction of HCN4 with Cav-3 ( xref ; xref ; xref )."
19351512
sparser
"We hypothesize that Cav3 associates with HCN4 and regulates the function of HCN4 channel."
19238754
sparser
"However, it is still unknown if HCN4 associates with Cav3."
19238754
reach
"P104L does not disrupt the association between Cav3 and HCN4."
19238754
CAV3 activates HCN4.
| 4
CAV3 activates HCN4. 4 / 4
| 4
reach
"Cav3 or P104L Modulates Properties of the HCN4 Channel."
19238754
reach
"Conclusions Our results indicate that HCN4 channel function is modulated by cav-3."
28648120
reach
"Whole cell patch clamp studies revealed that WT Cav3 and dominant negative and trafficking deficient mutation P104L modulate properties of HCN4 channels."
19238754
reach
"Our patch clamp experiments show that Cav3 modulates the HCN4 channel properties in the HEK293 cell line stably expressing the HCN4 channel."
19238754
CAV3 increases the amount of HCN4.
| 3
Modified CAV3 increases the amount of HCN4. 2 / 2
| 2
reach
"Also, coexpression of Cav3 with HCN4 enhanced I HCN4 density (XREF_FIG) and also increased the surface membrane expression of HCN4 protein (XREF_FIG)."
19238754
reach
"The greater signal on the antibiotin blot for the HCN4 + Cav3 lane relative to HCN4 + P104L suggests that P104L coexpression leads to the reduction of surface membrane expression of HCN4, in comparison to Cav3 coexpression, which in fact increased the surface membrane expression of HCN4."
19238754
CAV3 increases the amount of HCN4. 1 / 1
| 1
reach
"siRNA mediated knockdown of Cav-3 protein significantly decreased HCN1 and HCN4 expression."
27122250
CAV3 inhibits HCN4.
| 1
CAV3 inhibits HCN4. 1 / 1
| 1
reach
"Results WT cav-3 significantly decreased HCN4 current density and shifted midpoint of activation into negative direction."
28648120
PPP2 affects HCN4
| 13
PPP2 inhibits HCN4.
| 8
PPP2 inhibits HCN4. 8 / 8
| 8
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"We found that PP2 can inhibit HCN4 currents by negatively shifting the voltage dependence of channel activation, decreasing the whole cell channel conductance, and slowing activation and deactivation kinetics."
17977941
reach
"In human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed isoproterenol stimulation of HCN4 and inhibited HCN4-573x, a cAMP-insensitive human HCN4 mutant."
25658311
reach
"PP2 also slowed HCN4 activation kinetics regardless of ISO."
24566462
reach
"PP2 inhibited HCN4 and prevented the enhancement of HCN4 by ISO."
24566462
reach
"To confirm this conclusion, we needed to provide direct evidence for a well established ISO stimulation of HCN4 that is inhibited by PP2."
24566462
reach
"Our previous study showed PP2 inhibition of HCN4 activity by shifting its activation curve to more negative potentials."
24566462
reach
"Finally, in human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed the enhancement of HCN4 channels by isoproterenol and inhibited 573x, a cyclic adenosine momophosphate-insensitive human HCN4 mutant."
24566462
reach
"In human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed isoproterenol stimulation of HCN4 and inhibited HCN4-573x, a cAMP insensitive human HCN4 mutant."
24566462
PPP2 dephosphorylates HCN4.
| 2
PPP2 leads to the dephosphorylation of HCN4 on tyrosine. 2 / 2
| 2
reach
"PP2 at 10muM can nearly abolish the tyrosine phosphorylation of HCN4 after 30min incubation."
24566462
reach
"In this work, we showed that PP2 significantly reduced tyrosine phosphorylation of HCN4 in isolated sinus node myocytes (4B, green, compared to 4A, green)."
24566462
PPP2 phosphorylates HCN4.
| 1
PPP2 phosphorylates HCN4 on tyrosine. 1 / 1
| 1
reach
"We previously found a time dependent PP2 induced decrease in tyrosine phosphorylation of HCN4 channel proteins in HEK293."
24566462
PPP2 decreases the amount of HCN4.
| 1
PPP2 decreases the amount of HCN4. 1 / 1
| 1
reach
"PP2 suppression of HCN4 surface expression can explain PP2 prevention of ISO stimulation of I f."
24566462
PPP2 activates HCN4.
| 1
PPP2 activates HCN4. 1 / 1
| 1
reach
"PP2 induced an internalization of HCN4 associated with a decreased tyrosine phosphorylation."
24566462
HCN4 affects 3',5'-cyclic AMP
| 13
HCN4 binds 3',5'-cyclic AMP.
| 10
3',5'-cyclic AMP binds HCN4. 10 / 10
| 10
reach
"Sympathetic stimulation increases cAMP in SAMs, and binding of cAMP to HCN4 channels shifts pore opening to more depolarized membrane potentials and slows channel closing."
31756134
reach
"Sympathetic stimulation increases cAMP in SAMs, and binding of cAMP to HCN4 channels shifts pore opening to more depolarized membrane potentials and slows channel closing."
31756134
reach
"In contrast to knockout of RyR2, NCX or CaMKII function, or Ankyrin-B, or mutations in human RyRs, genetic manipulation in mice including HCN2 or HCN4 (general or cardiac specific SA node and AV node) knock outs, or inhibition of cAMP binding to HCN4 subunits, have minimal or no effects on resting heart rate, or on increases in heart rate during exercise, or chronotropic effect of beta-AR stimulation (XREF_SUPPLEMENTARY)."
20203315
reach
"The study by Xu et al. first examined steady-state binding of cAMP to an isolated HCN4 C-linker-CNBD fragment (called CL-CNBD) by using two different equilibrium binding assays, isothermal titration calorimetry and fluorescence anisotropy."
23217679
reach
"Mice with a homozygous mutation of a single amino-acid exchange (R669Q) that prevented binding of cAMP to HCN4 channels, HCN4 R669Q and R669Q mice, are also embryonic lethal [XREF_BIBR]."
19573534
reach
"42 Similar observations were made in adult heterozygous knock-in mice expressing a cAMP binding deficient HCN4 subunit."
21499520
reach
"We studied the role of I (f) in mice, in which binding of cAMP to HCN4 channels was abolished by a single amino-acid exchange (R669Q)."
18219271
reach
"This depolarizing shift in voltage dependence appeared to result from direct binding of cAMP to HCN4 because it was eliminated by a point mutation (R669Q) at a conserved arginine in the CNBD that has been shown to disrupt cAMP binding to HCN4 and other cyclic nucleotide sensitive ion channels."
23109717
reach
"While cAMP binding to HCN4 modulates I f activation (XREF_FIG), studies in which either HCN2 or HCN4 channel were genetically modified in mice, and prior studies in which I f current was blocked in numerous species by ionic or pharmacological maneuvers, do not indicate that I f is required for the SANC basal beating rate, or for its modulation by beta-AR stimulation."
20156611
reach
"I (f) is produced by hyperpolarization activated cyclic nucleotide sensitive-4 (HCN4) channels, and it is widely believed that sympathetic regulation of I (f) occurs via direct binding of cAMP to HCN4, independent of phosphorylation."
21150293
HCN4 inhibits 3',5'-cyclic AMP.
| 2
HCN4 inhibits 3',5'-cyclic AMP. 1 / 1
| 1
reach
"Because HCN1 is minimally sensitive to cAMP and has a more positive V 1/2 than HCN4, it is conceivable that a relative decrease in HCN1 and increase in HCN4 expression in aged SAMs could contribute to the hyperpolarizing shift in V 1/2 and increased cAMP response."
28057842
Mutated HCN4 inhibits 3',5'-cyclic AMP. 1 / 1
| 1
reach
"To directly investigate the role of cAMP dependent regulation of hyperpolarization activated cyclic nucleotide activated (HCN) channels in SAN activity, we generated mice with heart specific and inducible expression of a human HCN4 mutation (573X) that abolishes the cAMP dependent regulation of HCN channels."
19570998
HCN4 activates 3',5'-cyclic AMP.
| 1
HCN4 activates 3',5'-cyclic AMP. 1 / 1
| 1
reach
"In heterologous cells, the C-terminal-truncated HCN2 protein co-assembles with HCN4 to form functional heteromeric HCN channels, which activate faster than homomeric HCN2 or homomeric HCN4 channels, and display properties similar to endogenous myocardial I (f) channels Taken together, these results suggest that functional myocardial I (f) channels reflect the heteromeric assembly of HCN2 and HCN4 subunits and further that the HCN4 subunit underlies the cAMP mediated regulation of cardiac I (f) channels."
19574228
HCN4 affects CAV3
| 5 8 2
CAV3 binds HCN4. 10 / 10
| 5 8 2
sparser
"The immunoprecipitation results indicated an association of HCN4 and Cav3 in the heart and in HEK293 cells."
19238754
reach
"Molecular and functional evidence of HCN4 and caveolin-3 interaction during cardiomyocyte differentiation from human embryonic stem cells."
23311301
sparser
"These results confirm that the HCN4 and Cav3 proteins may be associated with one another."
19238754
sparser
"Interestingly, studies have shown that Cav3 is associated with HCN4, and affects its function [ xref ]."
27807743
sparser
"We sought to determine whether HCN4 associates with Cav3 in the heart."
19238754
sparser
"We conclude that HCN4 associates with Cav3 to form a HCN4 macromolecular complex."
19238754
sparser
"A number of laboratories including ours have provided evidence that HCN4 channels are localized to caveolae based on the presence of HCN4 in low density membrane fractions along with Cav-3 as well as the specific interaction of HCN4 with Cav-3 ( xref ; xref ; xref )."
19351512
sparser
"We hypothesize that Cav3 associates with HCN4 and regulates the function of HCN4 channel."
19238754
sparser
"However, it is still unknown if HCN4 associates with Cav3."
19238754
reach
"P104L does not disrupt the association between Cav3 and HCN4."
19238754
NKX2-5 affects HCN4
| 1 9
NKX2-5 decreases the amount of HCN4.
| 4
NKX2-5 decreases the amount of HCN4. 3 / 3
| 3
reach
"During heart tube maturation, Nkx2.5 progressively represses expression of Hcn4, resulting in molecular delineation of a distinct, compact SA node region in the right atrium."
20581739
reach
"During embryogenesis, Pitx2c was shown to synergistically drive expression of natriuretic peptide A (Nppa) in the presence of the homeobox transcription factor, Nkx2.5 which in turn, suppressed the expression of the pacemaker channel gene, Hcn4, and the T-box transcription factor (Tbx3), gene, thus delineating contractile atrial myocardium from the sinoatrial node."
22934047
reach
"Nkx2.5 in the atrial myocardium suppresses the expression of pacemaker channel gene Hcn4 and T-box transcription factor Tbx3, restricting their expression domain to the forming Nkx2.5-negative sinoatrial node and sinus horns and defining a gene expression boundary between the atrium and SA node."
18598977
Modified NKX2-5 decreases the amount of HCN4. 1 / 1
| 1
reach
"It may therefore be speculated that high levels of Nkx2.5 in EPCs after knockdown of Gata4 downregulate Hcn4 expression to promote their differentiation into atrial myocytes."
30906456
NKX2-5 inhibits HCN4.
| 1 2
NKX2-5 inhibits HCN4. 2 / 2
| 1 2
reach
"In working atrial myocardium that lacks the repressive effects of Shox2, Nkx2.5 activates expression of chamber specific genes (Cx40/Cx43/ANF) and represses SAN specific genes (Tbx3 and HCN4) to prevent ectopic pacemaker formation."
22628576
reach
"Nkx2-5 acts to repress Hcn4 and Tbx3, and is required to establish the SAN-atrial boundary [XREF_BIBR, XREF_BIBR]."
27770149
NKX2-5 increases the amount of HCN4.
| 2
NKX2-5 increases the amount of HCN4. 2 / 2
| 2
reach
"Since hypomorphism of Nkx2-5 causes augmentation of Hcn4 expression in the Nkx2-5 + / Shox2 + PV myocardium [XREF_BIBR], and that the Shox2 + / Hcn4 + SV myocardium is negative for Nkx2-5, it was proposed that Nkx2-5 inhibits pacemaker properties that belong to a primitive cell phenotype, and such effect is counter balanced by Shox2."
26682210
reach
"The results revealed that Nkx2.5 silencing increased HCN4 expression, decreased Cx40 expression and disrupted the expression of calcium handling proteins."
31798700
NKX2-5 activates HCN4.
| 1
NKX2-5 activates HCN4. 1 / 1
| 1
reach
"Although the loss of either Nkx2-5 or Pitx2 results in the ectopic pacemaker phenotype, inactivation of Pitx2 leads to an acquirement of the complete pacemaker program in the left SV-atrial junction, whereas haploinsufficiency of Nkx2-5 causes only an upregulation of Hcn4 in the Pitx2 + left sided structure, suggesting that these two genes repress pacemaker program through independently functional mechanisms [XREF_BIBR, XREF_BIBR]."
26682210
Ivabradine hydrochloride affects HCN4
| 1 8
Ivabradine hydrochloride inhibits HCN4.
| 1 6
Ivabradine hydrochloride inhibits HCN4. 6 / 6
| 1 6
reach
"Most interesting, a recent report (Bucchi et al., 2006) indicates that ivabradine blocks HCN1 in a use dependent manner via the closed state, but HCN4 via a voltage dependent, open state mechanism."
18162181
reach
"Properties of ivabradine induced block of HCN1 and HCN4 pacemaker channels."
16484306
reach
"In streptozotocin induced diabetic mice, ivabradine treatment significantly inhibited left ventricular hyperpolarization activated cyclic nucleotide gated channel 2 (HCN2) and HCN4 (major components of the I f current), activated PP2Ac, and attenuated NF-kappaB signaling activation and apoptosis, in line with improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia."
30998977
reach
"Given its clinical use, it is important to understand the molecular details of ivabradine block of HCN4 channels, the main isoform expressed in the pacemaker region of the heart."
23308150
reach
"Our findings confirm and extend observations in genetic conditions associated with altered HCN4 function and clinical trials with the HCN4 blocker ivabradine XREF_BIBR, XREF_BIBR."
29773827
reach
"HCN4 was blocked by the application of 2mM Cs + or 10muM ivabradine."
19729016
Ivabradine hydrochloride binds HCN4. 2 / 2
| 2
reach
"Ivabradine, which binds to the open HCN4 channel XREF_BIBR, XREF_BIBR, selectively slows sinus node diastolic depolarization while leaving sympathetic activation elsewhere in the heart unopposed XREF_BIBR, XREF_BIBR."
29773827
reach
"We therefore sought to investigate details of ivabradine induced block by identifying residues involved in the binding of ivabradine to HCN4, the HCN isoform most highly expressed in the sinoatrial node."
23308150
SRC affects HCN4
1 2 | 1 4
SRC activates HCN4.
1 | 1 3
SRC activates HCN4. 4 / 4
1 | 1 3
reach
"Src kinase phosphorylation accelerates activation of HCN2 and HCN4, whereas there are conflicting data if it also leads to a shift in the HCN4 activation curve [XREF_BIBR, XREF_BIBR]."
25580535
reach
"The diminished stimulation by ISO in the presence of PP2 on I HCN4, sinus node I f, action potentials, and spontaneous beating rate, respectively, supported the hypothesis that ISO can increase the sinus node pacemaker activity via a cAMP independent, Src mediated stimulation of HCN4 activity by phosphorylation on tentative tyrosine residues in the C-linker of the channel protein."
24566462
reach
"These results demonstrate that Src tyrosine kinase enhances HCN4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics."
17977941
signor
"These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531."
17977941
SRC phosphorylates HCN4.
1 1 |
SRC phosphorylates HCN4 on Y531. 2 / 2
1 1 |
signor
"These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531."
17977941
biopax:phosphositeplus
No evidence text available
SRC binds HCN4.
| 1
SRC binds HCN4. 1 / 1
| 1
reach
"Coimmunoprecipitation experiments revealed that Src forms a complex with HCN4 in HEK293 cells and in rat ventricular myocytes."
16680072
HCN4 affects Heart Rate
| 7
HCN4 activates Heart Rate.
| 4
HCN4 activates Heart Rate. 4 / 4
| 4
reach
"We observed that HCN4 blockade with ivabradine reduced HR but did not impair sympathetic or parasympathetic baroreflex function."
26764413
reach
"We observed that HCN4 blockade with ivabradine reduces HR, leaving baroreflex HR and MSNA regulation intact."
26764413
reach
"We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact."
26764413
reach
"HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact."
26764413
HCN4 inhibits Heart Rate.
| 3
HCN4 inhibits Heart Rate. 2 / 2
| 2
reach
"Beat-to-beat HR variability was reduced by HCN4 overexpression and enhanced by HCN4 knockdown."
29315578
reach
"We observed several distinct alterations in protein expression or activity likely to impact HR in parallel : (1) Hcn4 mRNA was significantly downregulated in TG mice, suggesting TBC1D10C controls HR via regulation of I f; (2) CaMKII activity is reduced."
27667030
Mutated HCN4 inhibits Heart Rate. 1 / 1
| 1
reach
"Due to this property, HCN channels have been thought to play a critical role in the positive chronotropic effect of beta-adrenergic stimulation (DiFrancesco, 2010) However, genetic ablation of cAMP sensitivity of HCN4 as well as transgenic overexpression of mutant HCN4 (HCN4-573X-Tg) that produces dominant negative suppression of cAMP sensitivity in heteromeric HCN channels did not inhibit beta-adrenergic acceleration of the HR (Harzheim etal."
29315578
FSD1 affects HCN4
| 7
FSD1 decreases the amount of HCN4.
| 3
FSD1 decreases the amount of HCN4. 2 / 2
| 2
reach
"37 Relevant to the present discussion, down-regulation of miR-1 and miR-133 have been associated with increased protein levels of HCN2 and HCN4 in hypertrophic hearts, whereas transfection of miR-1 and miR-133 into angiotensin II stimulated neonatal cardiac myocytes prevented overexpression of HCN2 and HCN4."
18988904
reach
"MiR-1 and -133 exert inhibitory effects upon HCN2, while miR-1 is also able to downregulate HCN4 expression."
26005035
Modified FSD1 decreases the amount of HCN4. 1 / 1
| 1
reach
"Therefore, the overexpression of exogenous miR-1 and miR-133 is able to suppress HCN2 and HCN4 expression."
26005035
FSD1 activates HCN4.
| 3
FSD1 activates HCN4. 3 / 3
| 3
reach
"This finding confirms a previous report in which miR-1 was shown to decrease I f by targeting the pacemaker genes HCN2 and HCN4 in hypertrophic cardiomyocytes XREF_BIBR."
20733065
reach
"Down-regulation of miR-1 and miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart."
21961174
reach
"Down-regulation of miR-1 and miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart."
18458081
FSD1 inhibits HCN4.
| 1
FSD1 inhibits HCN4. 1 / 1
| 1
reach
"A recent report on microRNA inhibition of HCN has shown that the cardiac muscle specific miR-1 can suppress both HCN2 and HCN4 mRNA [XREF_BIBR]."
19236845
Crizotinib affects HCN4
| 6
Crizotinib inhibits HCN4. 6 / 6
| 6
reach
"Crizotinib also slowed HCN4 activation and shifted the activation curve to the left towards more hyperpolarized potentials."
28217366
reach
"Calculation of the average time constant (Tau) of channel activation revealed that crizotinib resulted in slower HCN4 channel activation at test potentials> = -115 mV (*, washout vs. crizo, p < 0.05) (XREF_FIG)."
28217366
reach
"The mechanism by which crizotinib inhibits HCN4 channels is beyond the scope of the current work but could involve either direct channel effects or indirect effects through crizotinib 's effects on multiple tyrosine kinases."
28217366
reach
"Crizotinib inhibits hyperpolarization activated cyclic nucleotide gated channel 4 (HCN4) activity."
28217366
reach
"Furthermore, crizotinib significantly inhibited HCN4 channel activity, the major molecular determinant of I f."
28217366
reach
"Although we found that crizotinib inhibits HCN4 channel activity, it is a non selective channel inhibitor [XREF_BIBR, XREF_BIBR]."
28217366
SHOX2 affects HCN4
| 6
SHOX2 increases the amount of HCN4.
| 3
Modified SHOX2 increases the amount of HCN4. 3 / 3
| 3
reach
"In our previous study, it was confirmed that overexpression of Shox2 in cMSCs could upregulate HCN4 expression, and its level was significantly increased by co-culture induction."
27222368
reach
"The results demonstrated that overexpression of Shox2 significantly increased the expression of Tbx3, HCN4 and Cx45 at the mRNA (P < 0.05) and protein levels, and the difference increased markedly when co-cultured with RNCMs (XREF_FIG and XREF_FIG)."
27222368
reach
"At E10.5, despite of an unaltered Shox2 expression in the transgenic SAN, we observed a down-regulation of Tbx3, and a reduced but not absent Hcn4 expression (XREF_FIG), indicating that Shox2 does not regulate the expression of Tbx3 and Hcn4 directly in the SAN, consistent with the observation that Shox2 ectopic expression does not induce ectopic expression of Tbx3 and Hcn4 in the developing heart."
21640717
SHOX2 decreases the amount of HCN4.
| 2
SHOX2 decreases the amount of HCN4. 2 / 2
| 2
reach
"Shox2 -/- embryos have a reduced SAN size and exhibit increased expression of Nkx2.5, Cx40, and Cx43, and decreased expression of Hcn4, Tbx3, and Isl1 in the SAN primordium and show cardiac arrhythmias and embryonic lethality at day E11.5 [XREF_BIBR]."
29367536
reach
"Shox2 deficient embryos have markedly decreased SAN, dysfunctional cardiac pacemaker activity and reduced Hcn4 expression."
30906456
SHOX2 activates HCN4.
| 1
SHOX2 activates HCN4. 1 / 1
| 1
reach
"A previous study using mouse embryonic stem cells (embryoid bodies) performed by Hashem et al demonstrated that disruption of Shox2 downregulated Bmp4 and Hcn4, while addition of Bmp4 partially rescued this effect."
30906456
HCN4 affects mESC-CMs
| 6
HCN4 activates mESC-CMs. 6 / 6
| 6
reach
"The beating rate of hiPSC-CMs co-cultured with aggregates of HCN4 overexpressing mESC-CMs was significantly higher than that of non treated hiPSC-CMs and that of hiPSC-CMs co-cultured with aggregates of non overexpressing mESC-CMs."
26384234
reach
"Furthermore, HCN4 overexpressing mESC-CMs (HCN4 and EGFP mESC-CMs) showed a significantly larger I f current than did non overexpressing mESC-CMs (EGFP mESC-CMs) (XREF_FIG)."
26384234
reach
"HCN4 overexpressing mESC-CMs showed significantly more rapid beating than did non overexpressing mESC-CMs (Control mESC-CMs, 43.1 +/- 4.8 beats and min; HCN4 and EGFP mESC-CMs, 87.4 +/- 11.9 beats and min; EGFP mESC-CMs, 44.3 +/- 11.9 beats and min, n = 8 in each group, P < 0.0001) (XREF_FIG)."
26384234
reach
"HCN4 overexpressing mESC-CMs (HCN4 and EGFP mESC-CMs) expressed a 3-times higher level of Hcn4 than did non overexpressing mESC-CMs (EGFP mESC-CMs) (XREF_FIG)."
26384234
reach
"HCN4 overexpressing mESC-CMs showed significantly larger I f currents and more rapid spontaneous beating than did non overexpressing mESC-CMs."
26384234
reach
"(1) HCN4 overexpressing mESC-CMs expresses high levels of Hcn4 and Cacna1h genes and a low level of the Kcnj2 gene."
26384234
Pyraclofos affects HCN4
| 2 3
Pyraclofos activates HCN4. 5 / 5
| 2 3
sparser
"This shift would be smaller at voltages activating only HCN1 and larger at voltages which activate HCN4."
21456027
reach
"Voltage activation of HCN4 is most dramatically depolarized by the presence of cAMP, whereas HCN1 is minimally cAMP-reponsive."
21130878
sparser
"Voltage activation of HCN4 is most dramatically depolarized by the presence of cAMP, whereas HCN1 is minimally cAMP-reponsive."
21130878
reach
"As part of our ongoing studies of HCN4 channel regulation, we set out to describe the effects of cAMP on the voltage dependent activation of full-length mouse HCN4 channels."
23109717
reach
"The voltage dependent activation of HCN2 and HCN4 has been studied in HEK293 cells and different values for midpoint activation of HCN2 and HCN4 have been reported [XREF_BIBR - XREF_BIBR]."
19236845
MEF2 affects HCN4
| 1 4
MEF2 increases the amount of HCN4.
| 2
Modified mutated MEF2 increases the amount of HCN4. 2 / 2
| 2
reach
"Furthermore, overexpression of a dominant negative MEF2 mutant inhibited the enhancer activity of CNS13, decreased Hcn4 mRNA expression and also decreased the amplitude of I (h) current in myocytes isolated from the inflow tract of embryonic heart."
19477969
reach
"Overexpression of a dominant negative MEF2 mutant inhibits enhancer activity, decreases HCN4 mRNA expression and decreases If current amplitude, suggesting MEF2 may play a critical role in HCN4 transcription."
25145519
MEF2 binds HCN4.
| 1 1
MEF2 binds HCN4. 2 / 2
| 1 1
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"ChIP indicated that the binding of MEF2 to the HCN4 enhancer was not altered by Trx2 deletion; however, histone 3 acetylation at the MEF2 binding site was decreased, and expression of histone deacetylase 4 (HDAC4) was elevated following Trx2 deletion."
31751569
sparser
"ChIP indicated that the binding of MEF2 to the HCN4 enhancer was not altered by Trx2 deletion; however, histone 3 acetylation at the MEF2 binding site was decreased, and expression of histone deacetylase 4 (HDAC4) was elevated following Trx2 deletion."
31751569
MEF2 decreases the amount of HCN4.
| 1
Modified mutated MEF2 decreases the amount of HCN4. 1 / 1
| 1
reach
"Furthermore, overexpression of a dominant negative MEF2 mutant inhibited the enhancer activity of CNS13, decreased Hcn4 mRNA expression and also decreased the amplitude of I (h) current in myocytes isolated from the inflow tract of embryonic heart."
19477969
Spironolactone affects HCN4
| 4
Spironolactone decreases the amount of HCN4.
| 3
Spironolactone decreases the amount of HCN4. 3 / 3
| 3
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"Compared with the MI group, spironolactone significantly decreased the HCN4 mRNA expression in ischemic left ventricular myocardium by 16% (P < 0.05)."
26065643
reach
"In this study, we found that spironolactone significantly reduced HCN4 protein expression in rat ischemic left ventricular myocardium after MI, in agreement with Song et al.."
26065643
reach
"Compared with the MI group, spironolactone significantly downregulated the HCN2 and HCN4 protein expression in ischemic left ventricular myocardium by 50% and 52%, respectively (P < 0.05)."
26065643
Spironolactone increases the amount of HCN4.
| 1
Spironolactone increases the amount of HCN4. 1 / 1
| 1
reach
"Spironolactone diminishes spontaneous ventricular premature beats by reducing HCN4 protein expression in rats with myocardial infarction."
21468609
MiR-133 affects HCN4
| 4
MiR-133 decreases the amount of HCN4.
| 2
MiR-133 decreases the amount of HCN4. 1 / 1
| 1
reach
"37 Relevant to the present discussion, down-regulation of miR-1 and miR-133 have been associated with increased protein levels of HCN2 and HCN4 in hypertrophic hearts, whereas transfection of miR-1 and miR-133 into angiotensin II stimulated neonatal cardiac myocytes prevented overexpression of HCN2 and HCN4."
18988904
Modified miR-133 decreases the amount of HCN4. 1 / 1
| 1
reach
"Therefore, the overexpression of exogenous miR-1 and miR-133 is able to suppress HCN2 and HCN4 expression."
26005035
MiR-133 activates HCN4.
| 2
MiR-133 activates HCN4. 2 / 2
| 2
reach
"Down-regulation of miR-1 and miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart."
18458081
reach
"Down-regulation of miR-1 and miR-133 contributes to re-expression of pacemaker channel genes HCN2 and HCN4 in hypertrophic heart."
21961174
REST affects HCN4
| 4
REST increases the amount of HCN4.
| 2
REST increases the amount of HCN4. 2 / 2
| 2
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"XREF_BIBR - XREF_BIBR In earlier studies, we showed that a transcriptional repressor, NRSF, negatively regulates the expression of the HCN2 and HCN4 genes and that a transcriptional activator, MEF2, positively regulates HCN4 expression in cardiac myocytes."
23709563
reach
"By using genetically modified mice that express a dominant negative form of the transcriptional repressor neuron-restrictive silencing factor (dnNRSF-Tg), the authors generated a model of heart failure 11 : NRSF, a regulator of the fetal cardiac gene program, activates the reexpression of HCN2 and HCN4 to induce dilated cardiomyopathy."
23747794
REST inhibits HCN4.
| 1
REST inhibits HCN4. 1 / 1
| 1
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"In another set of experiments, we examined cardiac expression of the NRSF, which may repress HCN4 gene activity in cardiomyocytes [XREF_BIBR]."
19421833
REST activates HCN4.
| 1
REST activates HCN4. 1 / 1
| 1
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"In addition, we studied cardiac transcription of the neural restrictive silencer factor (NRSF) which is thought to repress HCN4 gene activity in cardiomyocytes [XREF_BIBR], of KCNE2, which may co-assemble and interact with HCN isotypes [XREF_BIBR], and of Kir2.1, shown to stabilize the resting potential of cardiomyocytes [XREF_BIBR, XREF_BIBR]."
19421833
HCN4 affects PSMD4
| 2 2
HCN4 binds PSMD4.
| 2 1
HCN4 binds PSMD4. 3 / 3
| 2 1
reach
"Recently, Duhme et al. demonstrated that altered C-linker interaction in hyperpolarized activated ion channel HCN4 is associated with familial TBS and AF, indicating that funny channel dysfunction contributes to the development of atrial tachyarrhythmias [XREF_BIBR]."
29843616
sparser
"Therefore, we sought to determine if genetic variation in the coding region of the HCN4 gene is associated with AF."
24607718
sparser
"HCN4 encodes for the cardiac pacemaker channel and HCN4 mutations are associated with familial sinus bradycardia and AF."
24607718
HCN4 inhibits PSMD4.
| 1
Mutated HCN4 inhibits PSMD4. 1 / 1
| 1
reach
"Loss-of-function HCN4 mutations are known to cause atrioventricular (AV) block, long QT syndrome (LQTS), AF, familial TBS and non compaction cardiomyopathy in addition to sinus bradycardia."
28204831
HCN4 affects CFI
| 1 3
HCN4 activates CFI.
| 2
HCN4 activates CFI. 2 / 2
| 2
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"HCN4 activity underlies the funny current (I f) that governs cardiac pacemaking, and mutations in HCN4 have been associated with various forms of sinus nodal dysfunction XREF_BIBR, XREF_BIBR."
22544366
reach
"The HCN4 channel is abundantly expressed in the sinoatrial (SA) node and cardiac conduction tissue, and underlies the funny current (I f)."
24607718
HCN4 inhibits CFI.
| 1
HCN4 inhibits CFI. 1 / 1
| 1
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"Finally, loss-of-function mutations in HCN4 leading to decreased I f and gain- or loss-of-function mutations in the transient receptor potential melastatin protein 4 gene (TRPM4) have also been implicated in BrS."
27803673
HCN4 binds CFI.
| 1
CACNA1A binds HCN4 and CFI. 1 / 1
| 1
sparser
"In response to stress-associated β-adrenergic stimulation, cyclic AMP (cAMP) is generated which binds directly to HCN4 and increases I f by shifted voltage-dependent activation."
28573409
BMP4 affects HCN4
| 4
BMP4 increases the amount of HCN4.
| 3
BMP4 increases the amount of HCN4. 3 / 3
| 3
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"The present results indicated that Bmp4 promotes Hcn4 expression via upregulation of Gata4, while transcription of Shox2 and Tbx3 was not affected by Bmp4."
30906456
reach
"It has been indicated that exogenous Bmp4 promotes the mRNA and protein expression of Hcn4, suggesting that Bmp4 is a critical factor in the differentiation of Tbx18 + EPCs into pacemaker like cells."
30906456
reach
"In vitro Bmp4 promoted the expression of Hcn4 in Tbx18 + EPCs via lineage tracing of Tbx18 : Cre and Rosa26R EYFP mice, which was likely due to upregulation of Gata4 expression."
30906456
BMP4 binds HCN4.
| 1
BMP4 binds HCN4. 1 / 1
| 1
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"In conclusion, the present study explored the association between Bmp4, Gata4 and Hcn4 in Tbx18 + EPCs and revealed that the expression of Nkx2.5 is regulated by Bmp4 and Gata4, providing important information for further studies."
30906456
MiRNA-1 affects HCN4
| 3
MiRNA-1 decreases the amount of HCN4.
| 2
MiRNA-1 decreases the amount of HCN4. 2 / 2
| 2
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"Furthermore, miRNA-1 suppression with antagomir-1 increased HCN2 and HCN4 protein levels; however, HCN2 and HCN4 mRNA levels were not affected, indicating that spironolactone stimulates miRNA-1 expression in the rat ischemic left ventricular myocardium after MI and that the upregulation of miRNA-1 expression partly contributes to the posttranscriptional repression of HCN protein expression."
26065643
reach
"MiRNA-1 suppression with antagomir-1 increased HCN2 and HCN4 protein levels; however, HCN2 and HCN4 mRNA levels were not affected."
26065643
MiRNA-1 inhibits HCN4.
| 1
MiRNA-1 inhibits HCN4. 1 / 1
| 1
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"Spironolactone significantly increased miRNA-1 levels and downregulated HCN2 and HCN4 protein and mRNA levels."
26065643
Lidocaine affects HCN4
| 1 2
Lidocaine inhibits HCN4. 3 / 3
| 1 2
sparser
"While it remains unknown if lidocaine inhibition of HCN2 and HCN4 is as sensitive to current and voltage as HCN1, there are noted differences in the inhibition of HCN1 and HCN4 isoforms by ivabradine, with only the latter being prominently current-dependent xref ."
28455536
reach
"While it remains unknown if lidocaine inhibition of HCN2 and HCN4 is as sensitive to current and voltage as HCN1, there are noted differences in the inhibition of HCN1 and HCN4 isoforms by ivabradine, with only the latter being prominently current dependent 31."
28455536
reach
"Lidocaine inhibited HCN1, HCN2, HCN1-HCN2, and HCN4 channel currents at 100 muM in both oocytes and/or HEK 293 cells; it caused a decrease in both tonic and maximal current (~ 30-50% inhibition) and slowed current activation kinetics for all subunits."
21303986
Bop affects HCN4
| 3
HCN4 binds bop. 3 / 3
| 3
sparser
"In addition, BrS has also been associated with HCN4, which encodes the hyperpolarization-activated cyclic nucleotide-gated potassium channel 4."
26566530
sparser
"HCN4 encodes the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 and was previously associated with BrS."
26230511
sparser
"Loss-of-function mutations in HCN4 have been associated with BrS but may be modulatory by acting to unmask BrS by reducing heart rate. xref "
29870068
TBX3 affects HCN4
| 3
TBX3 increases the amount of HCN4.
| 1
TBX3 increases the amount of HCN4. 1 / 1
| 1
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"HCN4 expression is specifically stimulated in SAN tissue by Tbx3, a transcriptional repressor whose activation is... " That both Tbx3 and the gene expression it controls are of vital importance to normal heart function during development does not indicate a primary role of HCN4 (I f) in rate control."
19361514
TBX3 decreases the amount of HCN4.
| 1
Modified TBX3 decreases the amount of HCN4. 1 / 1
| 1
reach
"Loss of Tbx3 in the SAN leads to expression of mature myocardium specific genes, while abnormal expression of Tbx3 upregulates the expression of Hcn4, forming a pacemaker in the atria."
30906456
TBX3 activates HCN4.
| 1
Mutated TBX3 activates HCN4. 1 / 1
| 1
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"Interestingly, although it has been established that Hcn4 is a repressive target of Nkx2-5 [XREF_BIBR, XREF_BIBR], null mutation of Tbx3 does not cause downregulation of Hcn4, suggesting that Tbx3 is only partially required for the maintenance of the SAN program."
26682210
TBX18 affects HCN4
| 3
TBX18 increases the amount of HCN4.
| 2
TBX18 increases the amount of HCN4. 2 / 2
| 2
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"Furthermore, Tbx18 gene transfer in mature ventricular cardiomyocytes increases HCN4 channel expression and yields pacemaker activity [XREF_BIBR]."
26384234
reach
"In this study, the underlying mechanism responsible for this differentiation may involve upregulation of the HCN4 promoter by TBX18, which indirectly increases the expression of HCN4 and enhances the efficiency of the differentiation of ADSCs into pacemaker like cells."
27632938
TBX18 activates HCN4.
| 1
TBX18 activates HCN4. 1 / 1
| 1
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"In contrast, Tbx18 overexpression led to epigenetic activation of the HCN4 promoter (XREF_FIG), underlying heightened HCN4 function in Tbx18-NRVMs (XREF_FIG)."
23242162
SP1 affects HCN4
1 | 2
SP1 increases the amount of HCN4.
1 | 1
SP1 increases the amount of HCN4. 2 / 2
1 | 1
trrust
No evidence text available
19471099
reach
"The upregulation of HCN2 and HCN4 transcription was accompanied by pronounced elevations of Sp1 and silencing of Sp1 by siRNA prevented overexpression of HCN2 and HCN4 in hypertrophic cardiomyocytes."
19471099
SP1 activates HCN4.
| 1
SP1 activates HCN4. 1 / 1
| 1
reach
"Our data indicate that Sp1 drives HCN2 and HCN4 transcription and determines the functional level of HCN2 and HCN4 mRNAs, and upregulation of Sp1 underlie the abnormal re-expression of HCN2 and HCN4 genes in hypertrophied myocytes."
19471099
RANGRF affects HCN4
| 3
Modified RANGRF increases the amount of HCN4. 2 / 2
| 2
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"Consistently, overexpression of mog1 by injection of mog1 mRNA markedly increased the expression of hcn4, but did not have any effect on expression of kcnj2, cav1.3 or scn5a (XREF_FIG)."
26903377
reach
"We then showed that knockdown of mog1 expression in zebrafish caused a decrease of hcn4 expression without affecting expression of other ion channel genes, including kcnj2, cav1.3 or scn5a."
26903377
RANGRF increases the amount of HCN4. 1 / 1
| 1
reach
"Mechanistically, knockdown of mog1 decreases expression of hcn4 involved in the regulation of the HR, and reduces expression of nkx2.5, gata4 and hand2 involved in cardiac morphogenesis."
26903377
PSMD4 affects HCN4
| 2 1
HCN4 binds PSMD4. 3 / 3
| 2 1
reach
"Recently, Duhme et al. demonstrated that altered C-linker interaction in hyperpolarized activated ion channel HCN4 is associated with familial TBS and AF, indicating that funny channel dysfunction contributes to the development of atrial tachyarrhythmias [XREF_BIBR]."
29843616
sparser
"Therefore, we sought to determine if genetic variation in the coding region of the HCN4 gene is associated with AF."
24607718
sparser
"HCN4 encodes for the cardiac pacemaker channel and HCN4 mutations are associated with familial sinus bradycardia and AF."
24607718
LGALS1 affects HCN4
| 3
LGALS1 inhibits HCN4.
| 2
LGALS1 inhibits HCN4. 2 / 2
| 2
reach
"GBP Reduces HCN4 Channel Function in PV + Inhibitory Neurons in Mouse Spinal Cord."
28871229
reach
"We provide evidence that GBP can reduce human HCN4 channel function by causing a hyperpolarizing shift in the voltage of activation."
28871229
LGALS1 binds HCN4.
| 1
HCN4 binds LGALS1. 1 / 1
| 1
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"Further, efforts aimed at understanding the structural-function relationship of GBP binding to HCN4 channels will help in this endeavor."
28871229
ISO affects HCN4
| 3
ISO activates HCN4. 3 / 3
| 3
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"In the presence of PP2, ISO (0.1 muM) was unable to induce a positive shift of HCN4 activation (C) in contrast to ISO stimulation of HCN4 (XREF_SUPPLEMENTARY)."
24566462
reach
"To confirm this conclusion, we needed to provide direct evidence for a well established ISO stimulation of HCN4 that is inhibited by PP2."
24566462
reach
"PP2 inhibited HCN4 and prevented the enhancement of HCN4 by ISO."
24566462
HCN4 affects nodal
| 3
HCN4 inhibits nodal.
| 1
HCN4 inhibits nodal. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 binds nodal.
| 1
HCN4 binds nodal. 1 / 1
| 1
reach
"It should be noted that because Xnr-1 is upstream of Lefty, Pitx2, and BMP-4, it is possible that HCN4 interacts with Xnr-1 primarily, and subsequent changes in gene expression are a result of disrupted Xnr-1 signaling."
28702127
HCN4 activates nodal.
| 1
HCN4 activates nodal. 1 / 1
| 1
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"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 affects cell differentiation
| 3
HCN4 activates cell differentiation. 3 / 3
| 3
reach
"We conclude that HCN2 and HCN4 channel isoforms, but not HCN1 and HCN3, promote the differentiation of PC12 cells toward sympathetic neurons."
31616252
reach
"It may therefore be speculated that high levels of Nkx2.5 in EPCs after knockdown of Gata4 downregulate Hcn4 expression to promote their differentiation into atrial myocytes."
30906456
reach
"In this study, the underlying mechanism responsible for this differentiation may involve upregulation of the HCN4 promoter by TBX18, which indirectly increases the expression of HCN4 and enhances the efficiency of the differentiation of ADSCs into pacemaker like cells."
27632938
HCN4 affects cell death
| 3
HCN4 activates cell death.
| 2
HCN4 activates cell death. 1 / 1
| 1
reach
"Preliminary data in my laboratory indicate that inducible, cardiac specific HCN4 KO indeed leads to rate slowing and death (not shown)."
19361514
Mutated HCN4 activates cell death. 1 / 1
| 1
reach
"The HCN-4 mutation caused both inherited sinus bradycardia, death during early embryogenesis, and other rhythmic disturbances in experimental animals, which clearly indicates the relevance of the funny channels in the disturbance of the cardiac rhythm by gene- or cell based therapeutic approaches."
29225577
HCN4 binds cell death.
| 1
Cell death binds HCN4. 1 / 1
| 1
reach
"DNA sequencing of all 8 exons and intron and exon junctions of the HCN2 gene revealed no nonsynonymous variants in the HCN2 gene.This study describes a large cohort of SIDS cases with genetic screening for variants in the 2 HCN isoforms most expressed in the heart, HCN2 and HCN4, which have been previously associated with cardiac arrhythmias and sudden death."
23623143
HCN4 affects bop
| 3
HCN4 binds bop. 3 / 3
| 3
sparser
"In addition, BrS has also been associated with HCN4, which encodes the hyperpolarization-activated cyclic nucleotide-gated potassium channel 4."
26566530
sparser
"HCN4 encodes the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 and was previously associated with BrS."
26230511
sparser
"Loss-of-function mutations in HCN4 have been associated with BrS but may be modulatory by acting to unmask BrS by reducing heart rate. xref "
29870068
HCN4 affects SSS
| 3
Mutated HCN4 activates SSS. 3 / 3
| 3
reach
"To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS)."
28803248
reach
"Despite recent reports on the complications of atrial fibrillation (AF) and left ventricular noncompaction (LVNC) in patients with SSS caused by HCN4 mutations, their overall clinical spectrum remains unknown."
28104484
reach
"A missense HCN4 mutation was found to lead to impaired trafficking of the channel to the surface membrane, resulting in SSS, long QT and torsade de pointes."
28204831
HCN4 affects PITX2
| 3
HCN4 activates PITX2.
| 2
HCN4 activates PITX2. 2 / 2
| 2
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
reach
"Blocking of HCN4 channels (both pharmacologically and physiologically) induces a significant decrease in Pitx2 signal in its anterior-posterior spread and area of the signal."
28818840
HCN4 inhibits PITX2.
| 1
HCN4 inhibits PITX2. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 affects CAV1
| 1 3
CAV1 binds HCN4. 2 / 2
| 1 2
sparser
"The elucidation of the molecular details of HCN4-cav-1 interaction can provide novel information to understand the basis of cardiac phenotypes associated with some forms of caveolinopathies."
22659290
sparser
"CBD alteration also caused a significant decrease of current density, due to a weaker HCN4-cav-1 interaction and accumulation of cytoplasmic channels."
22659290
CAV1 binds HCN4, KCNH2, and KCNJ2. 1 / 1
| 1
sparser
"Together with the findings that caveolin-1 interacts with potassium channels Kir2.1, KCNH2, and HCN4 and sodium channels Nav1.5 and Nav1.8, CAV1 becomes a strong candidate susceptibility gene for AF across different ethnic populations."
25953654
HCN4 affects BMP4
| 3
HCN4 inhibits BMP4.
| 1
HCN4 inhibits BMP4. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 binds BMP4.
| 1
BMP4 binds HCN4. 1 / 1
| 1
reach
"In conclusion, the present study explored the association between Bmp4, Gata4 and Hcn4 in Tbx18 + EPCs and revealed that the expression of Nkx2.5 is regulated by Bmp4 and Gata4, providing important information for further studies."
30906456
HCN4 activates BMP4.
| 1
HCN4 activates BMP4. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 affects Ala-Val
| 3
HCN4 activates Ala-Val.
| 2
Mutated HCN4 activates Ala-Val. 1 / 1
| 1
reach
"Loss-of-function HCN4 mutations are known to cause atrioventricular (AV) block, long QT syndrome (LQTS), AF, familial TBS and non compaction cardiomyopathy in addition to sinus bradycardia."
28204831
HCN4 activates Ala-Val. 1 / 1
| 1
reach
"Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4 mediated atrioventricular (AV) block."
24492017
HCN4 inhibits Ala-Val.
| 1
HCN4 inhibits Ala-Val. 1 / 1
| 1
reach
"Interestingly, knock-out of HCN4 not only causes sinus bradycardia, but also high-degree AV block, suggesting that I f also plays an important role in normal AVN conduction."
26140724
GATA4 affects HCN4
| 3
GATA4 increases the amount of HCN4.
| 1
GATA4 increases the amount of HCN4. 1 / 1
| 1
reach
"Not only did knockdown of Gata4 significantly downregulate Hcn4 mRNA expression compared with the control group (P < 0.05; XREF_FIG), but Nkx2.5 mRNA expression was significantly and Nkx2.5 protein expression was markedly upregulated (P < 0.05; XREF_FIG)."
30906456
GATA4 binds HCN4.
| 1
HCN4 binds GATA4. 1 / 1
| 1
reach
"In conclusion, the present study explored the association between Bmp4, Gata4 and Hcn4 in Tbx18 + EPCs and revealed that the expression of Nkx2.5 is regulated by Bmp4 and Gata4, providing important information for further studies."
30906456
GATA4 activates HCN4.
| 1
GATA4 activates HCN4. 1 / 1
| 1
reach
"Knockdown of Gata4 caused a downregulation of Hcn4 and an upregulation of Nkx2.5, but had no effect on Bmp4 expression."
30906456
ERBB affects HCN4
| 3
ERBB decreases the amount of HCN4.
| 2
ERBB decreases the amount of HCN4. 2 / 2
| 2
reach
"Three weeks after induction, reverse transcription-polymerase chain reaction analysis revealed that inhibition of NRG-1 and ErbB signaling (using AG1478) greatly enhanced the expression of HCN4, Tbx3, and Tbx2."
24390172
reach
"Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and alpha-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time dependent manner."
23606057
ERBB increases the amount of HCN4.
| 1
ERBB increases the amount of HCN4. 1 / 1
| 1
reach
"Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and alpha-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time dependent manner."
23606057
CAV1 affects HCN4
| 1 3
CAV1 binds HCN4. 2 / 2
| 1 2
sparser
"The elucidation of the molecular details of HCN4-cav-1 interaction can provide novel information to understand the basis of cardiac phenotypes associated with some forms of caveolinopathies."
22659290
sparser
"CBD alteration also caused a significant decrease of current density, due to a weaker HCN4-cav-1 interaction and accumulation of cytoplasmic channels."
22659290
CAV1 binds HCN4, KCNH2, and KCNJ2. 1 / 1
| 1
sparser
"Together with the findings that caveolin-1 interacts with potassium channels Kir2.1, KCNH2, and HCN4 and sodium channels Nav1.5 and Nav1.8, CAV1 becomes a strong candidate susceptibility gene for AF across different ethnic populations."
25953654
Propofol affects HCN4
| 2
Propofol inhibits HCN4. 2 / 2
| 2
reach
"Cacheaux et al. found that clinically relevant concentrations of propofol inhibited I h or slowed activation kinetics of HCN1, HCN2, and HCN4 in heterologous cells, with the greatest effect on HCN1."
21130878
reach
"Propofol inhibited and slowed the activation of recombinant HCN1, HCN2, and HCN4 channels at clinically relevant concentrations, in which the HCN1 current was the most sensitive of the three."
21642950
MiR-423-5p affects HCN4
| 2
HCN4 binds miR-423-5p. 2 / 2
| 2
reach
"These findings demonstrate a specific interaction between miR-423-5p and HCN4, and the predicted recognition elements identified in the HCN4 3 '-UTR contribute to this."
28821541
reach
"Interaction between miR-423-5p and HCN4 was confirmed by a dose dependent reduction in HCN4 3 '-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements)."
28821541
Isoprenaline affects HCN4
| 2
Isoprenaline activates HCN4. 2 / 2
| 2
reach
"In human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed isoproterenol stimulation of HCN4 and inhibited HCN4-573x, a cAMP-insensitive human HCN4 mutant."
25658311
reach
"In human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed isoproterenol stimulation of HCN4 and inhibited HCN4-573x, a cAMP insensitive human HCN4 mutant."
24566462
Hsa-miR-6811-5p affects HCN4
2 |
Transcriptionally active hsa-miR-6811-5p decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
22012620
biopax:mirtarbase
No evidence text available
21572407
Hsa-miR-6511b-5p affects HCN4
2 |
Transcriptionally active hsa-miR-6511b-5p decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
22012620
biopax:mirtarbase
No evidence text available
21572407
Hsa-miR-5589-3p affects HCN4
2 |
Transcriptionally active hsa-miR-5589-3p decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
22012620
biopax:mirtarbase
No evidence text available
21572407
Hsa-miR-557 affects HCN4
2 |
Transcriptionally active hsa-miR-557 decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
22012620
biopax:mirtarbase
No evidence text available
21572407
Hsa-miR-507 affects HCN4
2 |
Transcriptionally active hsa-miR-507 decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
21572407
biopax:mirtarbase
No evidence text available
22012620
Hsa-miR-4801 affects HCN4
2 |
Transcriptionally active hsa-miR-4801 decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
22012620
biopax:mirtarbase
No evidence text available
21572407
Hsa-miR-4748 affects HCN4
2 |
Transcriptionally active hsa-miR-4748 decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
21572407
biopax:mirtarbase
No evidence text available
22012620
Hsa-miR-4731-3p affects HCN4
2 |
Transcriptionally active hsa-miR-4731-3p decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
22012620
biopax:mirtarbase
No evidence text available
21572407
Hsa-miR-4464 affects HCN4
2 |
Transcriptionally active hsa-miR-4464 decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
21572407
biopax:mirtarbase
No evidence text available
22012620
Hsa-miR-329-5p affects HCN4
2 |
Transcriptionally active hsa-miR-329-5p decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
22012620
biopax:mirtarbase
No evidence text available
21572407
Hsa-miR-1-3p affects HCN4
2 |
Transcriptionally active hsa-miR-1-3p decreases the amount of HCN4. 2 / 2
2 |
biopax:mirtarbase
No evidence text available
18458081
biopax:mirtarbase
No evidence text available
18668037
Dronedarone affects HCN4
| 2
Dronedarone inhibits HCN4. 2 / 2
| 2
reach
"Besides fast Na (+) and Ca (2+) channels, dronedarone also inhibits HCN4 currents."
21279331
reach
"Human HCN4 channels expressed in CHO cells were blocked by dronedarone with an IC (50) of 1.0 +/-0.1 muM."
21279331
NPPA affects HCN4
| 2
NPPA activates HCN4. 2 / 2
| 2
reach
"While additional electrophysiological and global gene expression studies are required to validate the physiological nature of ANP induced VCS cells, we provided evidence that ANP treatment can increase the gene expression of the important VCS markers (HCN4 and Cx40) in embryonic ventricular cells through the NPRA/cGMP/PKG signal transduction pathway."
29720615
reach
"Collectively, these results indicate that ANP and NPRA signaling can modulate the relative distribution of HCN4 or Cx40 positive cell fractions within the embryonic ventricular cell cultures."
29720615
MEF2A affects HCN4
| 2
MEF2A increases the amount of HCN4. 2 / 2
| 2
reach
"Although we did not directly test for an interaction between HDAC and Mef2 on the R2R3 enhancer and there are other possible mechanisms that might explain our findings, one unifying hypothesis is that activation of Hcn4 expression by Mef2 is regulated by HDAC activity."
23085412
reach
"Transgenic overexpression of a dominant negative Mef2 protein causes a reduction in Hcn4 levels in the embryonic heart."
23085412
Histone affects HCN4
| 1 1
Histone demethylates HCN4.
| 1
Histone demethylates HCN4. 1 / 1
| 1
reach
"Notch1 Mediated Histone Demethylation of HCN4 Contributes to Aconitine induced Ventricular Myocardial Dysrhythmia."
32234357
Histone binds HCN4.
| 1
Histone binds HCN4 and MEF2C. 1 / 1
| 1
sparser
"Chromatin immunoprecipitation (ChIP) studies showed that testosterone enhanced recruitment of AR to the regulatory regions of MEF2C and HCN4 genes, which was associated with increased histone acetylation."
23598283
HCN4 affects tribromosalicylanilide
| 2
Mutated HCN4 inhibits tribromosalicylanilide. 1 / 1
| 1
reach
"Loss-of-function HCN4 mutations are known to cause atrioventricular (AV) block, long QT syndrome (LQTS), AF, familial TBS and non compaction cardiomyopathy in addition to sinus bradycardia."
28204831
Tribromosalicylanilide binds HCN4. 1 / 1
| 1
reach
"Recently, Duhme et al. demonstrated that altered C-linker interaction in hyperpolarized activated ion channel HCN4 is associated with familial TBS and AF, indicating that funny channel dysfunction contributes to the development of atrial tachyarrhythmias [XREF_BIBR]."
29843616
HCN4 affects miR-423-5p
| 2
HCN4 binds miR-423-5p. 2 / 2
| 2
reach
"These findings demonstrate a specific interaction between miR-423-5p and HCN4, and the predicted recognition elements identified in the HCN4 3 '-UTR contribute to this."
28821541
reach
"Interaction between miR-423-5p and HCN4 was confirmed by a dose dependent reduction in HCN4 3 '-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements)."
28821541
HCN4 affects localization
| 2
HCN4 inhibits localization.
| 1
HCN4 inhibits localization. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 activates localization.
| 1
HCN4 activates localization. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 affects krit1
| 2
HCN4 inhibits krit1. 2 / 2
| 2
reach
"We demonstrate that HCN4 channels attenuate the parasympathetic response of the SAN, and stabilize the spontaneous firing of the SAN."
29315578
reach
"Our study suggests that HCN4 channels attenuate the vagal response of the SAN, and thereby stabilize the spontaneous firing of the SAN."
29315578
HCN4 affects ivabradine hydrochloride
| 2
Ivabradine hydrochloride binds HCN4. 2 / 2
| 2
reach
"Ivabradine, which binds to the open HCN4 channel XREF_BIBR, XREF_BIBR, selectively slows sinus node diastolic depolarization while leaving sympathetic activation elsewhere in the heart unopposed XREF_BIBR, XREF_BIBR."
29773827
reach
"We therefore sought to investigate details of ivabradine induced block by identifying residues involved in the binding of ivabradine to HCN4, the HCN isoform most highly expressed in the sinoatrial node."
23308150
HCN4 affects ion channel
| 1 1
HCN4 inhibits ion channel.
| 1
HCN4 inhibits ion channel. 1 / 1
| 1
reach
"To test these possibilities, the effect of blockade of Na v 1.5 and HCN4 on the spontaneous activity of right atrial preparations was investigated -- if the age dependent decrease in the intrinsic heart rate is the result of a decline in either I Na or I f, blockade of the corresponding ion channel should have a smaller effect on the heart rate in the older animal."
19729016
HCN4 binds ion channel.
| 1
HCN4 binds ion channel. 1 / 1
| 1
sparser
"The ion channels formed by Hcn4 channel proteins are required to generate the current of pacemaker cells, which has a critical role in spontaneous depolarization."
30906456
HCN4 affects MEF2
| 1 1
MEF2 binds HCN4. 2 / 2
| 1 1
reach
"ChIP indicated that the binding of MEF2 to the HCN4 enhancer was not altered by Trx2 deletion; however, histone 3 acetylation at the MEF2 binding site was decreased, and expression of histone deacetylase 4 (HDAC4) was elevated following Trx2 deletion."
31751569
sparser
"ChIP indicated that the binding of MEF2 to the HCN4 enhancer was not altered by Trx2 deletion; however, histone 3 acetylation at the MEF2 binding site was decreased, and expression of histone deacetylase 4 (HDAC4) was elevated following Trx2 deletion."
31751569
HCN4 affects Lefty1
| 2
HCN4 inhibits Lefty1.
| 1
HCN4 inhibits Lefty1. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 activates Lefty1.
| 1
HCN4 activates Lefty1. 1 / 1
| 1
reach
"Both overexpressing HCN4 and injection of dominant negative HCN4 mRNA disrupt the localization of key morphogenetic patterning genes, Xnr-1, Lefty, Pitx2, and BMP-4, resulting in hearts with incorrect positional orientation and morphology."
28702127
HCN4 affects Ile-His
| 2
HCN4 activates Ile-His. 2 / 2
| 2
reach
"A comparison of Ih properties in VNO neurons with those of heterologously expressed hyperpolarization activated cyclic nucleotide gated (HCN) channels, together with RT-PCR experiments in VNO, indicate that Ih is caused by HCN2 and/or HCN4 subunits."
18509074
reach
"HCN4 knockdown decreased osteoclastic Ih and promoted osteoclastogenesis in the presence of zinc, but not in the absence of zinc."
25762086
HCN4 affects GCGR
| 2
HCN4 decreases the amount of GCGR. 2 / 2
| 2
reach
"Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4 directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart."
29107282
reach
"As the structurally related glucagon receptor (Gcgr) has been localized to the mouse SAN XREF_BIBR and like GLP-1, transduces an acute increase in HR XREF_BIBR, we examined whether Hcn4 Cre mice would enable reduction of atrial Gcgr expression."
29107282
ErbB receptors affects HCN4
| 2
ErbB receptors increases the amount of HCN4.
| 1
ErbB receptors increases the amount of HCN4. 1 / 1
| 1
reach
"Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and alpha-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time dependent manner."
23606057
ErbB receptors decreases the amount of HCN4.
| 1
ErbB receptors decreases the amount of HCN4. 1 / 1
| 1
reach
"Inhibition of ErbB receptors with AG1478 significantly decreased the percentage of beating EBs; down-regulated the gene expressions of Nkx2.5, GATA4, MLC-2v, ANF, and alpha-actin; and concomitantly up-regulated the gene expressions of HCN4 and Tbx3 in a time dependent manner."
23606057
AGL11 affects HCN4
| 2
AGL11 activates HCN4. 2 / 2
| 2
reach
"These results are in agreement with the previous findings that the main sites (Y531 and Y554) that mediate STK enhancement of HCN4 are located in the C-linker, excluding the CNBD and the distal C-terminal region."
24566462
reach
"Increased STK activity increases HCN4 activity associated with an enhanced surface expression and tyrosine phosphorylation of the channel protein, whereas inhibited STK activity by PP2 decreases HCN4 channel conductance associated with a decreased tyrosine phosphorylation of the channel proteins."
24566462
ADRB2 affects HCN4
| 2 1 1
ADRB2 binds HCN4.
| 2 1
HCN4 binds ADRB2. 1 / 1
| 2 1
sparser
"Furthermore, it was recently shown that the β2AR forms protein complexes with the funny-current ion channel HCN4, responsible for spontaneous depolarization of pacemaker cells."
26527381
ADRB2 activates HCN4.
| 1
ADRB2 activates HCN4. 1 / 1
| 1
reach
"In addition, the beta 2 -adrenergic receptor modulation of the HCN4 channel is lost when caveolae are disrupted using the cholesterol chelating drug MbetaCD consistent with a co-localization of beta 2 -adrenergic receptors and HCN4 channels in caveolae."
19351512
Zinc-finger affects HCN4
| 1
Zinc-finger activates HCN4. 1 / 1
| 1
reach
"Myocardial specific deletion of the carboxyl zinc-finger of Gata6 induces loss of HCN4 staining in the compact atrioventricular (AV) node with some retention of HCN4 staining in the AV bundle, but has no significant effect on the connexin40 positive bundle branches."
25613430
Tribromosalicylanilide affects HCN4
| 1
Tribromosalicylanilide binds HCN4. 1 / 1
| 1
reach
"Recently, Duhme et al. demonstrated that altered C-linker interaction in hyperpolarized activated ion channel HCN4 is associated with familial TBS and AF, indicating that funny channel dysfunction contributes to the development of atrial tachyarrhythmias [XREF_BIBR]."
29843616
Transcriptional activator affects HCN4
| 1
Transcriptional activator increases the amount of HCN4. 1 / 1
| 1
reach
"XREF_BIBR - XREF_BIBR In earlier studies, we showed that a transcriptional repressor, NRSF, negatively regulates the expression of the HCN2 and HCN4 genes and that a transcriptional activator, MEF2, positively regulates HCN4 expression in cardiac myocytes."
23709563
Testosterone affects HCN4
| 1
Testosterone increases the amount of HCN4. 1 / 1
| 1
reach
"In summary, testosterone upregulated cardiomyogenic transcription factor and HCN4 expression in stem cells."
23598283
Tamoxifen affects HCN4
| 1
Tamoxifen inhibits HCN4. 1 / 1
| 1
reach
"(Deep bradycardia, conduction defects, and high mortality of the tamoxifen induced HCN4 knockout in mice in XREF_FIG -study were not manifested in XREF_FIG -study which used much lower doses of tamoxifen)."
21925131
TTA protein affects HCN4
| 1
Modified tTA protein increases the amount of HCN4. 1 / 1
| 1
reach
"In this system, the HCN4-promoter drives the expression of tTA protein, which activates the transcription of HCN4 from the tetracycline responsive element (TRE)-CMV promoter with high efficiency."
29315578
Start affects HCN4
| 1
Start inhibits HCN4. 1 / 1
| 1
reach
"However, this possibility seems unlikely because, although the alternative start site reported by XREF_BIBR eliminated the cAMP sensitivity of HCN4 in HEKs, it did not relieve autoinhibition."
23109717
Soluble intracellular factors affects HCN4
| 1
Soluble intracellular factors inhibits HCN4. 1 / 1
| 1
reach
"As discussed above, our data from excised membrane patches excludes the possibility that soluble intracellular factors could cause the relief of autoinhibition of HCN4 in CHO cells."
23109717
Phenylephrine affects HCN4
| 1
Phenylephrine binds HCN4. 1 / 1
| 1
reach
"HCN4 Increases Rebound Burst Firing and Burst Duration in TC Neurons."
30877792
Peptide hormone affects HCN4
| 1
Peptide hormone activates HCN4. 1 / 1
| 1
reach
"The peptide hormone angiotensin II, which is upregulated in a number of cardiac pathologies and a known activator of PLD2, stimulates ERC trafficking of HCN4 channels."
18326556
Okadaic acid affects HCN4
| 1
Okadaic acid activates HCN4. 1 / 1
| 1
reach
"While OA significantly enhanced HCN4 expressing cells at 100muM, it failed to increase either Cntn2 : EGFP + or HCN4 + / Cntn2 : EGFP + double positive cells (XREF_SUPPLEMENTARY A)."
26028533
Nodal affects HCN4
| 1
HCN4 binds nodal. 1 / 1
| 1
reach
"It should be noted that because Xnr-1 is upstream of Lefty, Pitx2, and BMP-4, it is possible that HCN4 interacts with Xnr-1 primarily, and subsequent changes in gene expression are a result of disrupted Xnr-1 signaling."
28702127
Mog1 MOs affects HCN4
| 1
Mog1 MOs decreases the amount of HCN4. 1 / 1
| 1
reach
"Because mog1 MOs reduced the expression levels of hcn4 and transcriptional factor genes nkx2.5, gata4, and hand2, respectively, it is likely that abnormal cardiac looping and a decreased HR caused by MOs may be two independent events."
26903377
Mevastatin affects HCN4
| 1
Mevastatin activates HCN4. 1 / 1
| 1
reach
"Tail currents were too small in HCN4 expressing cells treated with mevastatin to reliably enable us to determine steady-state activation properties."
26404789
MESCs affects HCN4
| 1
MESCs activates HCN4. 1 / 1
| 1
reach
"Since CMs differentiated from a stable transgenic cell line of mESCs overexpressing HCN4 showed significantly more rapid beating capability 31, we also investigated if bio engineered pacemaker cells could be developed from differentiated ESC-CMs by an acute upregulation of I f."
28623610
Ion channel affects HCN4
| 1
HCN4 binds ion channel. 1 / 1
| 1
sparser
"The ion channels formed by Hcn4 channel proteins are required to generate the current of pacemaker cells, which has a critical role in spontaneous depolarization."
30906456
Inositol affects HCN4
| 1
Inositol increases the amount of HCN4. 1 / 1
| 1
reach
"Treatment with spironolactone prevented the MI induced increase of HCN4 protein levels (1.47 +/- 0.16 vs. 1.81 +/- 0.21, P < 0.05)."
21468609
Hsa-miR-192-5p affects HCN4
1 |
Transcriptionally active hsa-miR-192-5p decreases the amount of HCN4. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
19074876
Hsa-miR-133b affects HCN4
1 |
Transcriptionally active hsa-miR-133b decreases the amount of HCN4. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
18458081
Hsa-miR-133a-3p affects HCN4
1 |
Transcriptionally active hsa-miR-133a-3p decreases the amount of HCN4. 1 / 1
1 |
biopax:mirtarbase
No evidence text available
18458081
Gabapentin affects HCN4
| 1
Gabapentin activates HCN4. 1 / 1
| 1
reach
"Gabapentin Modulates HCN4 Channel Voltage-Dependence."
28871229
EpiC affects HCN4
| 1
EpiC increases the amount of HCN4. 1 / 1
| 1
reach
"Accordingly, EpiC increased the expression of the pacemaker channel subunit HCN4 (XREF_SUPPLEMENTARY)."
23284745
EmrE affects HCN4
| 1
HCN4 binds emrE. 1 / 1
| 1
sparser
"In all mESCs, cardiac differentiation was performed well via EB formation with or without HCN4 overexpression."
26384234
Doxycycline affects HCN4
| 1
Doxycycline decreases the amount of HCN4. 1 / 1
| 1
reach
"Furthermore, the transcription of HCN4 could be completely suppressed by doxycycline (DOX), which interferes with the binding of tTA to TRE."
29315578
Cytidine-3',5'-cyclic monophosphate affects HCN4
| 1
Cytidine-3',5'-cyclic monophosphate activates HCN4. 1 / 1
| 1
reach
"Other endogenous cyclic nucleotides can modulate HCN channels : when tested on recombinant channels expressed in HEK293 cells, cytidine-3 ',5 '-cyclic monophosphate (cCMP) activates HCN2 and HCN4, but not HCN1 and HCN3 [XREF_BIBR]."
26975509
Cre affects HCN4
| 1
Cre activates HCN4. 1 / 1
| 1
reach
"Similarly, Cre activation at gastrulation (E6.0) and early crescent stage (E7.0) of Hcn4 +/FHF cells demonstrated a demarcation between labeling events in the IVS and the LV with the LV but not IVS being labeled when tamoxifen was injected at E7.0 [XREF_BIBR]."
29367554
Cholesterol affects HCN4
| 1
Cholesterol decreases the amount of HCN4. 1 / 1
| 1
reach
"In our hands, cholesterol depletion reduced the expression of HCN4 at the channel membrane (XREF_FIG) and disrupts the expression of endogenous caveolin-1 in CHO-K1 cells, however, this did not lead to a redistribution of channels into non raft domains (XREF_FIG)."
26404789
Cell death affects HCN4
| 1
Cell death binds HCN4. 1 / 1
| 1
reach
"DNA sequencing of all 8 exons and intron and exon junctions of the HCN2 gene revealed no nonsynonymous variants in the HCN2 gene.This study describes a large cohort of SIDS cases with genetic screening for variants in the 2 HCN isoforms most expressed in the heart, HCN2 and HCN4, which have been previously associated with cardiac arrhythmias and sudden death."
23623143
Cation affects HCN4
| 1
Cation activates HCN4. 1 / 1
| 1
sparser
"The hyper polarization-gated cyclic nucleotide cation-activated channel Hcn4 , a SAN specific molecular marker ( xref ; xref ), is expressed as early as E7.5 in mouse embryo, initially in the sinus horns of the sinus venosus, and becomes restricted to the SAN by E12.5 ( xref )."
21640717
Carvedilol affects HCN4
| 1
Carvedilol inhibits HCN4. 1 / 1
| 1
reach
"Carvedilol inhibited HCN4 in a concentration dependent manner with an EC 50 value of 4.4 muM."
30098004
Calcium(2+) affects HCN4
| 1
Calcium(2+) inhibits HCN4. 1 / 1
| 1
reach
"Besides fast Na (+) and Ca (2+) channels, dronedarone also inhibits HCN4 currents."
21279331
CGMP subfamily affects HCN4
| 1
HCN4 binds cGMP subfamily. 1 / 1
| 1
sparser
"A recent crystal structure of the cytosolic C-terminal fragment of HCN4 bound to cGMP allowed the discovery of a new interaction site [ xref ], located at the interface between the CNBD and the C-linker."
26975509
CGMP affects HCN4
| 1
HCN4 binds cGMP. 1 / 1
| 1
reach
"A recent crystal structure of the cytosolic C-terminal fragment of HCN4 bound to cGMP allowed the discovery of a new interaction site [XREF_BIBR], located at the interface between the CNBD and the C-linker."
26975509
CCMP affects HCN4
| 1
CCMP activates HCN4. 1 / 1
| 1
reach
"Other endogenous cyclic nucleotides can modulate HCN channels : when tested on recombinant channels expressed in HEK293 cells, cytidine-3 ',5 '-cyclic monophosphate (cCMP) activates HCN2 and HCN4, but not HCN1 and HCN3 [XREF_BIBR]."
26975509
Berberine affects HCN4
| 1
Berberine inhibits HCN4. 1 / 1
| 1
reach
"Berberine attenuates spontaneous action potentials in sinoatrial node cells and the currents of human HCN4 channels expressed in Xenopus laevis oocytes."
25017321
Bepridil affects HCN4
| 1
Bepridil inhibits HCN4. 1 / 1
| 1
reach
"Amiodarone and bepridil potently inhibited the HCN4 channel current with IC50 values of 4.5 and 4.9 microM, respectively, which were close to their therapeutic concentrations."
19498275
Anti-HCN1 affects HCN4
| 1
HCN4 binds anti-HCN1. 1 / 1
| 1
reach
"Moreover, while the binding of anti-HCN1 and HCN4 antibodies produced dense stippling at two levels of the inner plexiform layer, HCN1 like immunoreactivity was more intense in the proximal level, and HCN4 like immunoreactivity was more intense in the distal level."
21456027
Amiodarone affects HCN4
| 1
Amiodarone inhibits HCN4. 1 / 1
| 1
reach
"Amiodarone and bepridil potently inhibited the HCN4 channel current with IC50 values of 4.5 and 4.9 microM, respectively, which were close to their therapeutic concentrations."
19498275
Alpha-MHC promoter affects HCN4
| 1
Alpha-MHC promoter activates HCN4. 1 / 1
| 1
reach
"Our observations are consistent with a recent study of a cardiac specific HCN4 gene KO mouse model wherein the alpha-MHC promoter linked Cre-Lox system of gene deletion induced substantial downregulation of HCN4 protein in the sinus node."
27313537
Aldosterone affects HCN4
| 1
Aldosterone activates HCN4. 1 / 1
| 1
reach
"Muto et al XREF_BIBR found that aldosterone promoted HCN2 and HCN4 mRNA and protein expression in cultured neonatal rat ventricular myocytes by binding to the mineralocorticoid receptor and that ABs (spironolactone and eplerenone) counteracted this effect."
26065643
Adrenergic receptor activity affects HCN4
| 1
Adrenergic receptor activity binds HCN4. 1 / 1
| 1
sparser
"Interestingly, S-SCAM has also been reported to interact with β 1 -adrenergic receptors (47) and HCN4 colocalizes with β 1 -adrenergic receptors in lipid rafts in the membranes of ventricular myocytes (48) ."
15980171
WAG-HCN1 channels affects HCN4
| 1
WAG-HCN1 channels inhibits HCN4. 1 / 1
| 1
reach
"Using co-expression experiments, we found that WAG-HCN1 channels suppress heteromeric HCN2 and HCN4 currents."
26578877
WAG-HCN1 affects HCN4
| 1
HCN4 binds WAG-HCN1. 1 / 1
| 1
reach
"These findings indicate that WAG-HCN1 directly interacts with HCN2 or HCN4 to decrease currents encoded by the respective heteromeric channels."
26578877
TXN2 affects HCN4
| 1
Modified TXN2 increases the amount of HCN4. 1 / 1
| 1
reach
"Loss of Trx2 reduces HCN4 expression via a mitochondrial ROS-HDAC4-MEF2C pathway and subsequently induces sick sinus syndrome in mice."
31751569
TFRC affects HCN4
| 1
TFRC decreases the amount of HCN4. 1 / 1
| 1
reach
"TR beta 1 exclusively suppressed HCN4 transcription."
19629520
T-box affects HCN4
| 1
T-box increases the amount of HCN4. 1 / 1
| 1
reach
"HCN4 expression is specifically stimulated in SAN tissue by T-box 3 (Tbx3), a transcriptional repressor whose activation is essential for development of the SAN and atrioventricular node (AV) bundle and segregation of pacemaker SAN from atrial cell lineages; this correlation further supports the view that HCN4 is a SAN marker gene [XREF_BIBR]."
19361514
S1 affects HCN4
| 1
S1 inhibits HCN4. 1 / 1
| 1
reach
"Replacement of leucine 272 in S1 of HCN4 by the corresponding phenylalanine present in HCN2 decreased tau act of HCN4 to 149 ms. Conversely, activation of the fast channel HCN2 was decreased 3-fold upon the corresponding mutation of F221L in the S1 segment."
12813043
S-LPS affects HCN4
| 1
HCN4 binds S-LPS. 1 / 1
| 1
reach
"Thus, binding of S-LPS to HCN4 most likely accounts for I f impairment in murine sinoatrial node cells XREF_BIBR and may contribute to reduction of beating rate in spontaneously active murine HL-1 cells XREF_BIBR."
24583250
R2R3 affects HCN4
| 1
R2R3 increases the amount of HCN4. 1 / 1
| 1
reach
"It will be interesting to determine if the increased activity of R2R3 in the setting of cardiac hypertrophy contributes to arrhythmogenicity by altering the domain of Hcn4 expression, and whether a specific interaction between class IIa HDACs and Mef2 directs this response."
23085412
Pitx2c affects HCN4
| 1
Pitx2c increases the amount of HCN4. 1 / 1
| 1
reach
"14 Wang et al. showed that Pitx2c deficient mice had increased expression of HCN4, TBX3, and SHOX2, all important for sinoatrial node formation."
24161141
PPY affects HCN4
| 1
PPY activates HCN4. 1 / 1
| 1
reach
"As HCN4 inward currents are augmented by low pH [XREF_BIBR], interstitial sodium influx through HCN4 may bolster depolarizing stimuli and generate pacemaker currents important for action potential generation in sour cells [XREF_BIBR]."
19284629
PPP3R1 affects HCN4
| 1
PPP3R1 activates HCN4. 1 / 1
| 1
reach
"This HCN4 TM-replacement preserved cAMP potentiation but augmented the magnitude of autoinhibition by the unliganded CNB fold; it moreover disrupted open-state trapping and Quick Activation so that autoinhibition became the dominant mechanism contributed by the C-terminal region to determine kinetics."
32146488
PITX2 affects HCN4
| 1
PITX2 decreases the amount of HCN4. 1 / 1
| 1
reach
"As discussed above, Pitx2 represses Hcn4 expression in the left atrium [XREF_BIBR] [XREF_BIBR]."
27139902
NRG1 affects HCN4
| 1
NRG1 decreases the amount of HCN4. 1 / 1
| 1
reach
"Three weeks after induction, reverse transcription-polymerase chain reaction analysis revealed that inhibition of NRG-1 and ErbB signaling (using AG1478) greatly enhanced the expression of HCN4, Tbx3, and Tbx2."
24390172
NPR1 affects HCN4
| 1
NPR1 activates HCN4. 1 / 1
| 1
reach
"Collectively, these results indicate that ANP and NPRA signaling can modulate the relative distribution of HCN4 or Cx40 positive cell fractions within the embryonic ventricular cell cultures."
29720615
NOG affects HCN4
1 |
Transcriptionally active NOG increases the amount of HCN4. 1 / 1
1 |
biopax:ctd
No evidence text available
27188386
NGLY1 affects HCN4
| 1
NGLY1 inhibits HCN4. 1 / 1
| 1
reach
"Our observations that HCN1- and HCN4 like immunoreactivities circumscribe dextran backfilled somata, and that PNGase F reduces the apparent molecular weight of both HCN1 and HCN4 by amounts consistent with the presence of glycosylated forms, agree well with previous reports that I h can be activated only in cells displaying surface membrane expression of HCN subunits and that glycosylation is required for surface membrane expression."
21456027
NGF affects HCN4
| 1
NGF decreases the amount of HCN4. 1 / 1
| 1
reach
"Results show that the HCN channel isoforms (HCN1-4) were all expressed in PC12 cells; blocking HCN channels with ivabradine suppressed NGF induced GAP-43 expression and neurite outgrowth; silencing the expression of HCN2 and HCN4 using silenced using small interfering RNAs (siRNA), rather than HCN1 and HCN3, restrained GAP-43 expression and neurite outgrowth, while overexpression of HCN2 and HCN4 channels with gene transfer promoted GAP-43 expression and neurite outgrowth."
31616252
MirP1 affects HCN4
| 1
MirP1 activates HCN4. 1 / 1
| 1
reach
"Along these lines, the K + channel ancillary subunit Mink related peptide 1 (MirP1), also termed KCNE2, enhances expression and speeds activation of HCN1, HCN2, and HCN4."
21945537
MicroRNA affects HCN4
| 1
MicroRNA activates HCN4. 1 / 1
| 1
reach
"MicroRNA 133a, for example, has been shown to target the ion-channel-encoding genes HCN2 and HCN4."
22042926
Leu-Val-Ser affects HCN4
| 1
Leu-Val-Ser activates HCN4. 1 / 1
| 1
reach
"The recombinant LVs mediated HCN4 gene is successfully transfected into rat BMSCs, and the expression of HCN4 protein and the pacemaker current can be detected."
24640376
LQTS-associated cav-3 mutations affects HCN4
| 1
LQTS-associated cav-3 mutations activates HCN4. 1 / 1
| 1
reach
"HCN4 current properties were differentially modulated by LQTS associated cav-3 mutations."
28648120
ISO (0.1 muM) affects HCN4
| 1
ISO (0.1 muM) activates HCN4. 1 / 1
| 1
reach
"In the presence of PP2, ISO (0.1 muM) was unable to induce a positive shift of HCN4 activation (C) in contrast to ISO stimulation of HCN4 (XREF_SUPPLEMENTARY)."
24566462
HDAC4 affects HCN4
| 1
HDAC4 binds HCN4. 1 / 1
| 1
sparser
"Moreover, HDAC4 binding to the HCN4 enhancer was mediated by MEF2."
31751569
HCN4-DN protein affects HCN4
| 1
HCN4-DN protein inhibits HCN4. 1 / 1
| 1
reach
"We confirmed that expression of HCN4-DN protein blocks HCN4 channel function and depolarizes the membrane voltage in Xenopus embryos."
28818840
HCN4 affects ventricular I f [
| 1
HCN4 inhibits ventricular I f [. 1 / 1
| 1
reach
"Knockout of HCN2 reduced sinoatrial I f by approximately 30% [XREF_BIBR], while a combined knockout of HCN2 and HCN4 caused a complete disruption of ventricular I f [XREF_BIBR]."
26141616
HCN4 affects pyraclofos
| 1
HCN4 activates pyraclofos. 1 / 1
| 1
reach
"Since cholesterol regulates a variety of ion channels important for cardiac function XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR, including rabbit HCN4 in which cholesterol depletion had previously been shown to modulate voltage dependence of activation and the kinetics of deactivation XREF_BIBR, we systematically examined the role of cholesterol in regulating the 3 human cardiac isoforms of HCN channels."
26404789
HCN4 affects phospholamban
| 1
HCN4 phosphorylates phospholamban. 1 / 1
| 1
reach
"To explain the restored maximal beating rate in response to maximal phosphodiesterase (PDE) inhibition, autonomic receptor stimulation, or infused cyclic adenosine monophosphate (cAMP), the model predicts that phospholamban phosphorylation by protein kinase A (PKA) and HCN 4 sensitivity to cAMP are altered in advanced age."
28887411
HCN4 affects phenylephrine
| 1
Phenylephrine binds HCN4. 1 / 1
| 1
reach
"HCN4 Increases Rebound Burst Firing and Burst Duration in TC Neurons."
30877792
HCN4 affects pattern specification process
| 1
HCN4 activates pattern specification process. 1 / 1
| 1
reach
"First, Hcn4-GFP + regions were masked to allow segmentation of alpha-actinin + / Hcn4-GFP - cells."
29352247
HCN4 affects pacemaker I f
| 1
HCN4 inhibits pacemaker I f. 1 / 1
| 1
reach
"[XREF_BIBR] Newer reports of gain of function mutations in KCNE3 [XREF_BIBR] and KCND3 [XREF_BIBR] (associated with outward potassium current channel), KCNJ8 causing increase in I KATP current, and HCN4 causing reduction of pacemaker I f current have been associated with BrS."
28928611
HCN4 affects melastatin protein 4 gene
| 1
HCN4 activates melastatin protein 4 gene. 1 / 1
| 1
reach
"Finally, loss-of-function mutations in HCN4 leading to decreased I f and gain- or loss-of-function mutations in the transient receptor potential melastatin protein 4 gene (TRPM4) have also been implicated in BrS."
27803673
HCN4 affects gain-
| 1
HCN4 inhibits gain-. 1 / 1
| 1
reach
"Finally, loss-of-function mutations in HCN4 leading to decreased I f and gain- or loss-of-function mutations in the transient receptor potential melastatin protein 4 gene (TRPM4) have also been implicated in BrS."
27803673
HCN4 affects emrE
| 1
HCN4 binds emrE. 1 / 1
| 1
sparser
"In all mESCs, cardiac differentiation was performed well via EB formation with or without HCN4 overexpression."
26384234
HCN4 affects cardiac I(f) channels
| 1
HCN4 activates cardiac I(f) channels. 1 / 1
| 1
reach
"In heterologous cells, the C-terminal-truncated HCN2 protein co-assembles with HCN4 to form functional heteromeric HCN channels, which activate faster than homomeric HCN2 or homomeric HCN4 channels, and display properties similar to endogenous myocardial I (f) channels Taken together, these results suggest that functional myocardial I (f) channels reflect the heteromeric assembly of HCN2 and HCN4 subunits and further that the HCN4 subunit underlies the cAMP mediated regulation of cardiac I (f) channels."
19574228
HCN4 affects calcium(2+)
| 1
HCN4 inhibits calcium(2+). 1 / 1
| 1
reach
"Representative Ca 2+ traces, shown in XREF_FIG, demonstrate that HCN2, but not HCN4, depletion abolished the kinase inhibitor induced Ca 2+ entry."
21037554
HCN4 affects cGMP subfamily
| 1
HCN4 binds cGMP subfamily. 1 / 1
| 1
sparser
"A recent crystal structure of the cytosolic C-terminal fragment of HCN4 bound to cGMP allowed the discovery of a new interaction site [ xref ], located at the interface between the CNBD and the C-linker."
26975509
HCN4 affects cGMP
| 1
HCN4 binds cGMP. 1 / 1
| 1
reach
"A recent crystal structure of the cytosolic C-terminal fragment of HCN4 bound to cGMP allowed the discovery of a new interaction site [XREF_BIBR], located at the interface between the CNBD and the C-linker."
26975509
HCN4 affects anti-HCN4 antibody
| 1
HCN4 inhibits anti-HCN4 antibody. 1 / 1
| 1
reach
"The HCN1 peptide immunogen suppressed binding of the anti-HCN1 antibody (data not illustrated), while the HCN4 fusion protein immunogen suppressed binding of the anti-HCN4 antibody."
21456027
HCN4 affects anti-HCN1
| 1
HCN4 binds anti-HCN1. 1 / 1
| 1
reach
"Moreover, while the binding of anti-HCN1 and HCN4 antibodies produced dense stippling at two levels of the inner plexiform layer, HCN1 like immunoreactivity was more intense in the proximal level, and HCN4 like immunoreactivity was more intense in the distal level."
21456027
HCN4 affects alpha-actinin
| 1
HCN4 activates alpha-actinin. 1 / 1
| 1
reach
"First, Hcn4-GFP + regions were masked to allow segmentation of alpha-actinin + / Hcn4-GFP - cells."
29352247
HCN4 affects adrenergic receptor activity
| 1
Adrenergic receptor activity binds HCN4. 1 / 1
| 1
sparser
"Interestingly, S-SCAM has also been reported to interact with β 1 -adrenergic receptors (47) and HCN4 colocalizes with β 1 -adrenergic receptors in lipid rafts in the membranes of ventricular myocytes (48) ."
15980171
HCN4 affects aconitine
| 1
HCN4 activates aconitine. 1 / 1
| 1
reach
"Notch1 Mediated Histone Demethylation of HCN4 Contributes to Aconitine induced Ventricular Myocardial Dysrhythmia."
32234357
HCN4 affects WAG-HCN1
| 1
HCN4 binds WAG-HCN1. 1 / 1
| 1
reach
"These findings indicate that WAG-HCN1 directly interacts with HCN2 or HCN4 to decrease currents encoded by the respective heteromeric channels."
26578877
HCN4 affects VCL
| 1
HCN4 activates VCL. 1 / 1
| 1
reach
"HCN2 and HCN4 channels increased 10-20 mV, and HCN1 only 5 mV."
27556324
HCN4 affects TFRC
| 1
HCN4 activates TFRC. 1 / 1
| 1
reach
"Protein expression of HCN2 and HCN4 increased from P7 to P90 in both rat strains (XREF_FIG)."
21945537
HCN4 affects TBC1D10C
| 1
HCN4 inhibits TBC1D10C. 1 / 1
| 1
reach
"We observed several distinct alterations in protein expression or activity likely to impact HR in parallel : (1) Hcn4 mRNA was significantly downregulated in TG mice, suggesting TBC1D10C controls HR via regulation of I f; (2) CaMKII activity is reduced."
27667030
HCN4 affects SRC
| 1
SRC binds HCN4. 1 / 1
| 1
reach
"Coimmunoprecipitation experiments revealed that Src forms a complex with HCN4 in HEK293 cells and in rat ventricular myocytes."
16680072
HCN4 affects S-LPS
| 1
HCN4 binds S-LPS. 1 / 1
| 1
reach
"Thus, binding of S-LPS to HCN4 most likely accounts for I f impairment in murine sinoatrial node cells XREF_BIBR and may contribute to reduction of beating rate in spontaneously active murine HL-1 cells XREF_BIBR."
24583250
HCN4 affects Pro-Val
| 1
HCN4 activates Pro-Val. 1 / 1
| 1
reach
"However, HCN4 channels are well placed to modulate the activity of PV + neurons that have been shown to be critical modulators of mechanical hypersensitivity that develops following nerve injury."
28871229
HCN4 affects Phase IV
| 1
HCN4 activates Phase IV. 1 / 1
| 1
reach
"The modulation of HCN4 gating would then increase Phase IV slope of the cardiac action potential and allow for earlier opening of L-type Ca 2+ channels, causing the sinoatrial node to " fire " more frequently in the presence of epinephrine and norepinephrine and with reductions of acetylcholine."
25589263
HCN4 affects N-carbamoylsarcosine
| 1
HCN4 activates N-carbamoylsarcosine. 1 / 1
| 1
reach
"However, this is because overexpression of wild-type HCN4 alone does not suffice to cause automaticity in adult LV CMs, probably due to the vast differences in ion channel panoplies as well as certain contentious beta-subunits between sinoatrial pacemaker cells and normally quiescent adult LV CMs."
19460073
HCN4 affects Leu-Val
| 1
HCN4 activates Leu-Val. 1 / 1
| 1
reach
"However, this is because overexpression of wild-type HCN4 alone does not suffice to cause automaticity in adult LV CMs, probably due to the vast differences in ion channel panoplies as well as certain contentious beta-subunits between sinoatrial pacemaker cells and normally quiescent adult LV CMs."
19460073
HCN4 affects LVNC
| 1
Mutated HCN4 activates LVNC. 1 / 1
| 1
reach
"In this study, although the genetic evidence for the involvement of the HCN4 mutations in the combined bradycardia-LVNC phenotype is very strong, and the electrophysiological data provide strong evidence for causality of the HCN4 mutations in the pathogenesis of the observed bradycardia, the mechanism whereby HCN4 mutations lead to LVNC remains unknown.For the first time, we link mutations in HCN4 to a combined phenotype of bradycardia and LVNC."
25145517
HCN4 affects LQT3
| 1
HCN4 activates LQT3. 1 / 1
| 1
reach
"Mutations in HCN4 can cause sinus node dysfunction and sick sinus syndrome, whereas mutations in SCN5A, CAV3, and CACNA1C are linked to sudden cardiac death, ventricular tachycardia, and long QT syndromes (LQT3, -8, and -9) (XREF_FIG)."
27766009
HCN4 affects LGALS1
| 1
HCN4 binds LGALS1. 1 / 1
| 1
reach
"Further, efforts aimed at understanding the structural-function relationship of GBP binding to HCN4 channels will help in this endeavor."
28871229
HCN4 affects I(f
| 1
HCN4 activates I(f. 1 / 1
| 1
reach
"These data suggested that different ratios of HCN2 and HCN4 transcripts overlapping in different tissues also contribute to the tissue specific properties of I (f)."
19236845
HCN4 affects Histone, and MEF2C
| 1
Histone binds HCN4 and MEF2C. 1 / 1
| 1
sparser
"Chromatin immunoprecipitation (ChIP) studies showed that testosterone enhanced recruitment of AR to the regulatory regions of MEF2C and HCN4 genes, which was associated with increased histone acetylation."
23598283
HCN4 affects HDAC4
| 1
HDAC4 binds HCN4. 1 / 1
| 1
sparser
"Moreover, HDAC4 binding to the HCN4 enhancer was mediated by MEF2."
31751569
HCN4 affects HCN2DeltaC
| 1
HCN4 binds HCN2DeltaC. 1 / 1
| 1
reach
"66 HCN2DeltaC lacks the C-terminal CNBD, and associates with HCN4 in both heart and heterologous cells upon coexpression."
20305382
HCN4 affects HCN channels
| 1
HCN4 activates HCN channels. 1 / 1
| 1
reach
"Our results suggest that HCN channels are mostly produced by the HCN4 isoform in heart, which contrasts with the sharp differences in the isoform stoichiometry in pituitary (15 HCN4 :2 HCN2 :1 HCN1 :1 HCN3), kidney (24 HCN4 :2 HCN3 :1 HCN2 :1 HCN1) and brain (3 HCN4 :2 HCN2 :1 HCN1 :1 HCN3)."
24234751
HCN4 affects HCN channel
| 1
HCN4 inhibits HCN channel. 1 / 1
| 1
reach
"Therefore, 10 microM of ZD7288 a selective antagonist of the HCN channel subtypes HCN1, HCN2 and HCN4 was applied to a subset of VGN identified as myelinated A-type (n = 5)."
20456426
HCN4 affects Gly-Gly-Ala
| 1
HCN4 inhibits Gly-Gly-Ala. 1 / 1
| 1
reach
"The HCN4 +/luc mice were identified by PCR using the forward primer 5 '-CGA GCT GGA CGG CGA CGT AAA CGG C-3 ' and reverse primer 5 '-CAT CCT TAG GGA GAA TTT GTT GAC C-3 '."
29315578
HCN4 affects GATA4
| 1
HCN4 binds GATA4. 1 / 1
| 1
reach
"In conclusion, the present study explored the association between Bmp4, Gata4 and Hcn4 in Tbx18 + EPCs and revealed that the expression of Nkx2.5 is regulated by Bmp4 and Gata4, providing important information for further studies."
30906456
HCN4 affects GAP43
| 1
Modified HCN4 increases the amount of GAP43. 1 / 1
| 1
reach
"Results show that the HCN channel isoforms (HCN1-4) were all expressed in PC12 cells; blocking HCN channels with ivabradine suppressed NGF induced GAP-43 expression and neurite outgrowth; silencing the expression of HCN2 and HCN4 using silenced using small interfering RNAs (siRNA), rather than HCN1 and HCN3, restrained GAP-43 expression and neurite outgrowth, while overexpression of HCN2 and HCN4 channels with gene transfer promoted GAP-43 expression and neurite outgrowth."
31616252
HCN4 affects GAA
| 1
HCN4 inhibits GAA. 1 / 1
| 1
reach
"The HCN4 +/luc mice were identified by PCR using the forward primer 5 '-CGA GCT GGA CGG CGA CGT AAA CGG C-3 ' and reverse primer 5 '-CAT CCT TAG GGA GAA TTT GTT GAC C-3 '."
29315578
HCN4 affects FST
| 1
HCN4 activates FST. 1 / 1
| 1
reach
"Previously known HCN4 channel mutations causing FSB were localized in the intracellular C-terminus region."
20662977
HCN4 affects CK2alpha
| 1
CK2alpha binds HCN4. 1 / 1
| 1
isi
"Furthermore, aconitine promoted the formation of a new regulatory complex containing NICD and KDM5A in a CK2alpha HI regime, which then targeted to HCN4 promoter and induced re-expression of HCN4 in mature cardiomyocytes."
32234357
HCN4 affects CCT_complex
| 1
HCN4 inhibits CCT_complex. 1 / 1
| 1
reach
"The HCN4 +/luc mice were identified by PCR using the forward primer 5 '-CGA GCT GGA CGG CGA CGT AAA CGG C-3 ' and reverse primer 5 '-CAT CCT TAG GGA GAA TTT GTT GAC C-3 '."
29315578
HCN4 affects BVES
| 1
BVES binds HCN4. 1 / 1
| 1
reach
"While I f was not investigated in the Popdc1 null mutant, therefore an interaction of POPDC1 and HCN4 can not be excluded, however, the similarity of phenotypes of both Popdc1 and Popdc2 null mutants makes it very unlikely that I f function is modulated by POPDC1."
29534001
HCN4 affects AR
| 1
HCN4 binds AR. 1 / 1
| 1
sparser
"A synthetic peptide derived from the β(2)AR-binding domain of the HCN4 channel disrupted interaction between HCN4 and β(2)AR."
22613709
HCN4 affects ADRB2
| 2 1
HCN4 binds ADRB2. 1 / 1
| 2 1
sparser
"Furthermore, it was recently shown that the β2AR forms protein complexes with the funny-current ion channel HCN4, responsible for spontaneous depolarization of pacemaker cells."
26527381
HCN2DeltaC affects HCN4
| 1
HCN4 binds HCN2DeltaC. 1 / 1
| 1
reach
"66 HCN2DeltaC lacks the C-terminal CNBD, and associates with HCN4 in both heart and heterologous cells upon coexpression."
20305382
Gbeta76C affects HCN4
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Gbeta76C inhibits HCN4. 1 / 1
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"We found that GBE irreversibly inhibited the HCN2 and HCN4 channel currents in aconcentration dependent fashion and that the HCN4 current was more sensitive to GBE compared with HCN2."
32435840
GATA6 affects HCN4
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GATA6 activates HCN4. 1 / 1
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"Myocardial specific deletion of the carboxyl zinc-finger of Gata6 induces loss of HCN4 staining in the compact atrioventricular (AV) node with some retention of HCN4 staining in the AV bundle, but has no significant effect on the connexin40 positive bundle branches."
25613430
FHF affects HCN4
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FHF decreases the amount of HCN4. 1 / 1
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"As the expression patterns of Hcn4 and Tbx5 are largely overlapping in the presumptive FHF [XREF_BIBR], these data suggest that the IVS is derived from FHF progenitor cells that have already started to downregulate Hcn4 expression at the early heart tube stage."
29367554
EDN1 affects HCN4
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EDN1 increases the amount of HCN4. 1 / 1
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"ET-1 increased the expression of HCN2 and HCN4 mRNA in a dose- and time dependent manner."
22985562
Cation_channels affects HCN4, and THY1
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Cation_channels binds THY1 and HCN4. 1 / 1
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sparser
"Coimmunoprecipitation, immunohistochemistry, confocal imaging, and patch-clamp recording were used to test for association of Thy1 and HCN4, a cation channel subunit, in adult rat retina."
22281825
CS affects HCN4
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CS inhibits HCN4. 1 / 1
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"HCN4 was blocked by the application of 2mM Cs + or 10muM ivabradine."
19729016
CPA1 affects HCN4
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CPA1 decreases the amount of HCN4. 1 / 1
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"Finally, the protein expression of HCN4 in HEK293 cells was markedly downregulated by CPA."
31982470
CK2alpha affects HCN4
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CK2alpha binds HCN4. 1 / 1
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"Furthermore, aconitine promoted the formation of a new regulatory complex containing NICD and KDM5A in a CK2alpha HI regime, which then targeted to HCN4 promoter and induced re-expression of HCN4 in mature cardiomyocytes."
32234357
CAV1 affects HCN4, KCNH2, and KCNJ2
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CAV1 binds HCN4, KCNH2, and KCNJ2. 1 / 1
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sparser
"Together with the findings that caveolin-1 interacts with potassium channels Kir2.1, KCNH2, and HCN4 and sodium channels Nav1.5 and Nav1.8, CAV1 becomes a strong candidate susceptibility gene for AF across different ethnic populations."
25953654
CACNA1A affects CFI, and HCN4
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CACNA1A binds HCN4 and CFI. 1 / 1
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sparser
"In response to stress-associated β-adrenergic stimulation, cyclic AMP (cAMP) is generated which binds directly to HCN4 and increases I f by shifted voltage-dependent activation."
28573409
BVES affects HCN4
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BVES binds HCN4. 1 / 1
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"While I f was not investigated in the Popdc1 null mutant, therefore an interaction of POPDC1 and HCN4 can not be excluded, however, the similarity of phenotypes of both Popdc1 and Popdc2 null mutants makes it very unlikely that I f function is modulated by POPDC1."
29534001
Aldosterone affects HCN4
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Aldosterone increases the amount of HCN4. 1 / 1
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"Aldosterone (24-h incubation) increases the expression of HCN2 protein (by 60.0%) and HCN4 protein (by 84.8%), but not HCN1 protein."
17644563
AR affects HCN4
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HCN4 binds AR. 1 / 1
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sparser
"A synthetic peptide derived from the β(2)AR-binding domain of the HCN4 channel disrupted interaction between HCN4 and β(2)AR."
22613709
AKAP4 affects HCN4
| 1
AKAP4 increases the amount of HCN4. 1 / 1
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"Furthermore, aconitine promoted the formation of a new regulatory complex containing NICD and KDM5A in a CK2alpha HI regime, which then targeted to HCN4 promoter and induced re-expression of HCN4 in mature cardiomyocytes."
32234357
AGT affects HCN4
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AGT activates HCN4. 1 / 1
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"The peptide hormone angiotensin II, which is upregulated in a number of cardiac pathologies and a known activator of PLD2, stimulates ERC trafficking of HCN4 channels."
18326556
ACTA2 affects BMP2, BMP4, CACNA2D2, HCN4, and NPPB
| 1
BMP2 binds BMP4, ACTA2, CACNA2D2, HCN4, and NPPB. 1 / 1
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sparser
"The observed interaction with the region of Nppb , Hcn4, Acta2, Cacna2d2, Bmp2 and Bmp4 suggests that T-box factors also directly regulate these genes (Fig.  xref b, c; Online Fig. 7)."
22130515
8-Br-cGMP affects HCN4
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8-Br-cGMP increases the amount of HCN4. 1 / 1
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"The addition of 8-Br-cGMP at 10microM and 100microM significantly increased the gene expression of HCN4 (3.4-fold and 5.3-fold respectively Vs. control, P < 0.005, Fig."
29720615