"SAP97 appeared to be largely distributed along Z-lines
In order to further test whether or not Kv1.5 and SAP97 directly interact in atrial and/or ventricular myocytes, we conducted co-immunoprecipitation experiments."
"Interestingly, SAP97 also interacts with the 3 last residues of Kv4.2/4.3 (Ser-Ala-Leu) and Kv1.5 (Thr-Asp-Val) to potentially target and/or anchor ion channels to cell surface [ xref – xref ]."
"But even if SAP97 does bind the Kv1.5 C-terminus under specific conditions, that fact cannot explain the lack of dependence of the SAP97-mediated current enhancement on the extreme Kv1.5 C-terminus."
"Indeed, given this stark difference in effects of SAP97 on most Kv1 channels versus its effect on Kv1.5, it would be surprising if SAP97 did in fact bind Kv1.5."
"Perhaps in COS-7 cells the state of the channel is permissive of a stable SAP97-Kv1.5 interaction that is not seen in other cell types (including heart)."
"SAP97 and Kv1.5 subunits can interact, directly or indirectly, both in the heart and in heterologous systems. xref , xref Adenoviral overexpression of SAP97 in neonatal rat atrial myocytes leads to clustering of endogenous Kv1.5 subunits at myocyte-myocyte contacts and an increase in both I Kur and the number of 4-aminopyridine-sensitive potassium channels in cell-attached membrane patches. xref On the other hand, pull-down and coimmunoprecipitation assays in cardiac myocytes showed that the Kv4 channel C terminus, SAP97, and CaMKII interact together, and that the interaction is suppressed by SAP97 silencing and enhanced by SAP97 overexpression. xref In HEK293 cells, SAP97 silencing reproduced the effects of CaMKII inhibition on current kinetics and suppressed Kv4/CaMKII interactions."
"The results presented here exclude a role of SAP97 binding to Kv1.5 in effecting the current enhancement and show that a specific N-terminal threonine residue (T15) is required in this phenomenon."
"In particular, overexpression of SAP97 increases surface levels of Kv1.5 XREF_BIBR, XREF_BIBR, XREF_BIBR and decreases other Kv channels 56, while CASK participates in the targeting of Kir2 channels 57."
"The function of CHIP in Kv1.5 protein regulation was first suggested by immunoprecipitation studies that showed interaction of CHIP with Kv1.5 proteins ( Fig. 1 A)."
"Cooperation of STUB1 and HSC70 may lead to enhanced ubiquitination of genes, for example, HSC70 is required for STUB1 to form a complex with Kv1.5 proteins [36] ."
"Our findings presented evidence that Kv1.5 is a substrate of CHIP, and that CHIP associates with Kv1.5 proteins to depress their expression and channel function."
"The interaction of CHIP with Kv1.5 was enhanced by overexpressed Hsc70 but depressed by siRNA against Hsc70 ( Fig. 6 B, bottom), indicating that Hsc70 is indispensable for the CHIP activity."
"Interaction with Kv1.5 of myc-CHIP ∆U was much less than that of myc-CHIP WT ( Fig. 5 B), whereas the interaction with Hsc70 remained unaltered ( Fig. 6 A, right panel)."
"SAP97 appeared to be largely distributed along Z-lines
In order to further test whether or not Kv1.5 and SAP97 directly interact in atrial and/or ventricular myocytes, we conducted co-immunoprecipitation experiments."
"Interestingly, SAP97 also interacts with the 3 last residues of Kv4.2/4.3 (Ser-Ala-Leu) and Kv1.5 (Thr-Asp-Val) to potentially target and/or anchor ion channels to cell surface [ xref – xref ]."
"But even if SAP97 does bind the Kv1.5 C-terminus under specific conditions, that fact cannot explain the lack of dependence of the SAP97-mediated current enhancement on the extreme Kv1.5 C-terminus."
"Indeed, given this stark difference in effects of SAP97 on most Kv1 channels versus its effect on Kv1.5, it would be surprising if SAP97 did in fact bind Kv1.5."
"Perhaps in COS-7 cells the state of the channel is permissive of a stable SAP97-Kv1.5 interaction that is not seen in other cell types (including heart)."
"SAP97 and Kv1.5 subunits can interact, directly or indirectly, both in the heart and in heterologous systems. xref , xref Adenoviral overexpression of SAP97 in neonatal rat atrial myocytes leads to clustering of endogenous Kv1.5 subunits at myocyte-myocyte contacts and an increase in both I Kur and the number of 4-aminopyridine-sensitive potassium channels in cell-attached membrane patches. xref On the other hand, pull-down and coimmunoprecipitation assays in cardiac myocytes showed that the Kv4 channel C terminus, SAP97, and CaMKII interact together, and that the interaction is suppressed by SAP97 silencing and enhanced by SAP97 overexpression. xref In HEK293 cells, SAP97 silencing reproduced the effects of CaMKII inhibition on current kinetics and suppressed Kv4/CaMKII interactions."
"The results presented here exclude a role of SAP97 binding to Kv1.5 in effecting the current enhancement and show that a specific N-terminal threonine residue (T15) is required in this phenomenon."
"The function of CHIP in Kv1.5 protein regulation was first suggested by immunoprecipitation studies that showed interaction of CHIP with Kv1.5 proteins ( Fig. 1 A)."
"Cooperation of STUB1 and HSC70 may lead to enhanced ubiquitination of genes, for example, HSC70 is required for STUB1 to form a complex with Kv1.5 proteins [36] ."
"Our findings presented evidence that Kv1.5 is a substrate of CHIP, and that CHIP associates with Kv1.5 proteins to depress their expression and channel function."
"The interaction of CHIP with Kv1.5 was enhanced by overexpressed Hsc70 but depressed by siRNA against Hsc70 ( Fig. 6 B, bottom), indicating that Hsc70 is indispensable for the CHIP activity."
"Interaction with Kv1.5 of myc-CHIP ∆U was much less than that of myc-CHIP WT ( Fig. 5 B), whereas the interaction with Hsc70 remained unaltered ( Fig. 6 A, right panel)."
"For an analysis of a frequency-dependent inhibition of Kv1.5 by sertraline without contamination of the decline of the current under control conditions, the relative currents (I Sertraline /I Control ) at 1 and 2 Hz were plotted ( xref )."
"The phospholipid composition of the cell may be different from human native cardiac myocytes and the differences of membrane composition may affect sertraline-induced Kv1.5 inhibition."
"The result of voltage-dependent inhibition of Kv1.5 by sertraline shows an additional low degree of inhibition detected in the voltage range positive to +10 mV despite Kv1.5 being fully activated at this voltage range ( xref )."
"To further investigate the time-dependent inhibition of Kv1.5 by sertraline, deactivation kinetics of Kv1.5 current was studied. xref shows the representative superimposed tail currents recorded with a 250-ms repolarizing pulse at –40 mV after a 250-ms depolarizing pulse of +50 mV from a holding potential of –80 mV, under control conditions and in the presence of 1 µM sertraline."
"In this study, the characteristics of the sertraline-induced inhibition of Kv1.5 suggest that sertraline preferentially interacts with the open state of Kv1.5 based on the following lines of evidence."
"The voltage-dependent inhibition of Kv1.5 by sertraline implies that the inhibition of Kv1.5 by sertraline occurs preferentially after the channels are open [ xref xref xref xref xref xref xref ]."
"A recent study of more than 300 patients with early-onset lone AF revealed 3 " gain-of-function " mutations in KCNA5 in addition to several loss-of-function mutations, supporting the hypothesis that AF susceptibility may be enhanced by either change in KCNA5 function."
"This engineered cell line designated KCNA5 fs/fs hence resembles the genotype of a well documented patient case of lone AF caused by a heterozygous but dominant KCNA5 nonsense mutation, to lead to a loss of K v 1.5 function."
"Recent studies however have shown that loss-of-function mutations in KCNA5, the gene that encodes K V 1.5, the alpha subunit of the I Kur channel, is associated with the development of AF and that inhibition of I Kur can promote the induction of AF in experimental models."
"Loss-of-function mutations in the related voltage gated potassium channel KCNA5 unexpectedly lead to AF by an atypical mechanism involving decreased I Kur which leads to a predisposition for atrial action potential prolongation and early after-depolarizations [XREF_BIBR, XREF_BIBR]."
"Indeed, a loss-of-function mutation in KCNA5 associated with AF results in decreased ultrarapid delayed rectifier potassium current ( I Kur ), prolongation of the atrial action potential, and facilitates early afterdepolarizations. xref Recent discoveries have also revealed mechanisms by which mutations in sodium channels may influence AF susceptibility."
"Important issues regarding the safety of I Kur blockers have been raised recently with the finding that loss-of-function mutations in KCNA5 are associated with familial AF. xref Because KCNA5 encodes the α subunit of the I Kur channel, these results suggest that a reduction in I Kur may predispose to the development of AF."
"The results of flow cytometry and Tunel assay experiments showed that Kv1.5 silencing induced apoptosis significantly, in contrast to several results reported previously [XREF_BIBR]."
"Overexpression of the human KCNA5 gene increases K+ currents (i.e., K+ efflux or loss), accelerates apoptotic volume decrease (AVD), increases caspase-3 activity, and induces apoptosis."
"The objective of this study was to test the hypothesis that overexpression of KCNA5, which encodes a delayed-rectifier voltage gated K+ (Kv) channel, increases K+ currents and enhances apoptosis."
"Silencing Kv1.5 expression in the osteosarcoma cells significantly inhibited the proliferation of osteosarcoma cells, induced cell cycle arrest at G0/G1 phase, and induced cell apoptosis through up-regulation of p21, p27, Bax, Bcl-XL and caspase-3 and down-regulation of cyclins A, cyclins D1, cyclins E, Bcl-2 and Bik."
"In contrast, overexpression of KCNA5 gene or attenuation of Kv1.5 downregulation XREF_BIBR, XREF_BIBR, XREF_BIBR reduces apoptosis during these diseases."
"Thus, a significant portion of the interaction between Kv1.5 and α-actinin-2 is mediated across a region where the N-terminus meets the core transmembrane domains of the protein."
"None yielded lacZ reporter gene activity above control, showing that there is little to no interaction between the C-terminus of Kv1.5 and α-actinin-2."
"We utilized the yeast two-hybrid lacZ reporter gene to estimate the relative strength of interaction between various domains in Kv1.5 and the α-actinin-2 interacting fragment."
"Notably, KMUP-1 reversed 5-HT-inhibited Kv1.5 protein and this effect was attenuated significantly by adding the PKC activator PMA, suggesting that KMUP-1 did modulate the 5-HT-mediated PKC pathway (Fig xref )."
"5-HT-inhibited Kv1.5 protein was unaffected by the PKA inhibitor KT5720 but significantly affected by the PKC inhibitor chelerythrine, suggesting that 5-HT is not involved in cross-talk with AC/PKA cascades xref , xref but exclusively involved in the PKC pathway in rat PASMCs."
"Notably, KMUP-1 reversed 5-HT-inhibited Kv1.5 protein and this response was significantly attenuated by co-incubation with the PKC activator PMA, suggesting that 5-HT-mediated PKC signaling can be modulated by KMUP-1."
"Taken together, KMUP-1 alone increased Kv1.5 and it also reversed 5-HT-inhibited Kv1.5 protein, suggesting that KMUP-1 is not simply an inhibitor of 5-HT-mediated PKC signaling, but might have the direct actions on AC/PKA pathways."
"Surprisingly, in addition to increases in Kv1.5 channel protein with KMUP-1, KMUP-1 also reversed 5-HT inhibition of Kv1.5 and this effect was markedly blunted in combination with the PKC activator PMA."
"5-HT inhibition of Kv1.5 protein was reversed by KMUP-1 (1 μM), chelerythrine (1 μM), KMUP-1+PMA (1 μM) or KMUP-1+chelerythrine, but not affected by the PKC activator PMA (1 μM)."
"Recent work has shown that the Src tyrosine kinase can physically associate with Kv1.5 to bring about its tyrosine kinase–dependent suppression ( Holmes et al. 1996 )."
"Using immunoprecipitation, we show that Kv1.5 is associated with Src family protein tyrosine kinases and that this association does not change with cell differentiation."
"Overexpression of the human KCNA5 gene increases K+ currents (i.e., K+ efflux or loss), accelerates apoptotic volume decrease (AVD), increases caspase-3 activity, and induces apoptosis."
"The objective of this study was to test the hypothesis that overexpression of KCNA5, which encodes a delayed-rectifier voltage gated K+ (Kv) channel, increases K+ currents and enhances apoptosis."
"Furthermore, ST induced apoptotic cell shrinkage was significantly accelerated in COS-7 cells and rat PASMC transfected with KCNA5, and blockade of KCNA5 channels with 4-aminopyridine (4-AP) reduced K+ currents through KCNA5 channels and inhibited ST induced apoptosis in KCNA5 transfected COS-7 cells."
"Moreover, voltage dependent potassium channels are also targeted by miRNAs - KCNA5 as a target of miR-1, KCNQ5 as a target of miR-190 and TASK1 as a target of miR-138."
"Recent work has shown that the Src tyrosine kinase can physically associate with Kv1.5 to bring about its tyrosine kinase–dependent suppression ( Holmes et al. 1996 )."
"Using immunoprecipitation, we show that Kv1.5 is associated with Src family protein tyrosine kinases and that this association does not change with cell differentiation."
"FHL1 also binds and regulates KCNA5, the key molecular component of the voltage gated K + channel (Kv1.5), responsible for repolarization of the human atrium after depolarization [65] and an important therapeutic target in the treatment of AF [66]."
"FHL1 also binds and regulates KCNA5, the key molecular component of the voltage-gated K + channel (Kv1.5), responsible for repolarization of the human atrium after depolarization [65] and an important therapeutic target in the treatment of AF [66] ."
"Overall, our finding indicated that KCNA5 protein may interact with Cav-1, thereby contributing to the proliferation and early transformation of mammary cells."
"Overall, our finding indicated that KCNA5 protein may interact with Cav-1, thereby contributing to the proliferation and early transformation of mammary cells."
"We found that expression of Cav-1 correlated with the expression of Kv channels in mammary epithelial cells (MCF10A, MCF10A-ST1, and MCF7), and silencing of Cav-1 inhibited the expression of KCNA5 (voltage gated shaker related subfamily A, member 5)."
"Our results implicate polycomb dependent epigenetic repression of KCNA5 as a key mechanism of channel inhibition and reveal the critical role of this inhibition in promoting cancer cell survival under conditions of microenvironmental stress, in particular hypoxic stress."
"We explored the effects of Kv1.5 silencing on proliferation and growth of osteosarcoma cells using CCK-8 and colony formation assays, and we found that Kv1.5 silencing significantly suppressed cell proliferation and growth after a 48-h treatment compared to the control-shRNA or untreated groups in MG-63 cells."
"Silencing Kv1.5 expression in the osteosarcoma cells significantly inhibited the proliferation of osteosarcoma cells, induced cell cycle arrest at G0/G1 phase, and induced cell apoptosis through up-regulation of p21, p27, Bax, Bcl-XL and caspase-3 and down-regulation of cyclins A, cyclins D1, cyclins E, Bcl-2 and Bik."
"We found that CREB knock-down by siRNA reduces Kv1.5, CREB binds to the Kv1.5 promoter in the heart, and CREB increases transcription of mouse and human Kv1.5 promoters."
"To determine if CREB binds to the Kv1.5 promoter in the heart, mouse ventricular tissue was homogenized and chromatin immunoprecipitation (ChIP) was performed with an anti-CREB antibody."
"Although this early work was suggestive, we have gone further by showing that CREB transfection increases the transcription of human and mouse Kv1.5 promoter reporter constructs, and that ChIP demonstrates binding of CREB to the Kv1.5 promoter in mouse heart."
"Overall, our finding indicated that KCNA5 protein may interact with Cav-1, thereby contributing to the proliferation and early transformation of mammary cells."
"Overall, our finding indicated that KCNA5 protein may interact with Cav-1, thereby contributing to the proliferation and early transformation of mammary cells."
"If, for example, actinin binding to Kv1.5 anchors the channel in the cell interior, SAP97 binding to an overlapping site in actinin could free the channel to traffic to the cell surface."
"We found that CREB knock-down by siRNA reduces Kv1.5, CREB binds to the Kv1.5 promoter in the heart, and CREB increases transcription of mouse and human Kv1.5 promoters."
"To determine if CREB binds to the Kv1.5 promoter in the heart, mouse ventricular tissue was homogenized and chromatin immunoprecipitation (ChIP) was performed with an anti-CREB antibody."
"Although this early work was suggestive, we have gone further by showing that CREB transfection increases the transcription of human and mouse Kv1.5 promoter reporter constructs, and that ChIP demonstrates binding of CREB to the Kv1.5 promoter in mouse heart."
"If, for example, actinin binding to Kv1.5 anchors the channel in the cell interior, SAP97 binding to an overlapping site in actinin could free the channel to traffic to the cell surface."
"Interaction with Kv1.5 of myc-CHIP ∆U was much less than that of myc-CHIP WT ( Fig. 5 B), whereas the interaction with Hsc70 remained unaltered ( Fig. 6 A, right panel)."
"The Kv1.5 and Kv2.1 K+-channel alpha subunits are constitutively tyrosine phosphorylated and physically associate with Fyn both in cultured SCs and in the sciatic nerve in vivo."
"It is known that mXinα interacts not only with cortactin ( xref ) but also with p120-catenin ( xref ) and β-catenin ( xref ), suggesting that mXinα may be required for the association of Kv1.5, cortactin, and N-cadherin."
"Considering all the exposure estimates, expression of TNF-α was associated with both water and urinary concentrations of arsenic, that of POLB was associated with nail and urinary levels, and that of KCNA5 was associated with water and nail levels (and was borderline significant with urinary arsenic)."
"Furthermore, the expression level of KCNA5 was also associated with nail arsenic concentrations, whereas that of TNF-α was also associated with urine arsenic concentrations."
"The Kv1.5 and Kv2.1 K+-channel alpha subunits are constitutively tyrosine phosphorylated and physically associate with Fyn both in cultured SCs and in the sciatic nerve in vivo."
"It is known that mXinα interacts not only with cortactin ( xref ) but also with p120-catenin ( xref ) and β-catenin ( xref ), suggesting that mXinα may be required for the association of Kv1.5, cortactin, and N-cadherin."
"Considering all the exposure estimates, expression of TNF-α was associated with both water and urinary concentrations of arsenic, that of POLB was associated with nail and urinary levels, and that of KCNA5 was associated with water and nail levels (and was borderline significant with urinary arsenic)."
"Furthermore, the expression level of KCNA5 was also associated with nail arsenic concentrations, whereas that of TNF-α was also associated with urine arsenic concentrations."
"In addition, levels of KCNA5 expression were found to be higher in a subset of ES tumors that did not express high levels of BMI-1, thus providing indirect evidence that BMI-1 might repress KCNA5 in ES (XREF_FIG)."
"As expected, increasing sulfenic acid with tBOOH, or trapping this modification with dimedone, significantly increased internalization of Kv1.5 (XREF_FIG)."
"Therefore, under acute oxidative stress, sulfenic acid modification triggers internalization of Kv1.5 and significantly reduces channel recycling back to the cell surface."
"In light of the previous evidence, the main goal of this report is to replicate the association of KCNA5 rs10744676 polymorphism with SSc and SSc-related PAH in an independent European population of Caucasian ancestry."
"# Ariadne: The transcription of a potassium channel gene, Kv1.5 , is regulated by glucocorticoids and cAMP in both GH3 cells and cardiac myocytes ( 16-18 ). [Expression]"
"A cAMP response element (CRE) consensus signal was identified in the 5'-noncoding region. cAMP regulates the expression of Kv1.5 gene in a cell-specific manner. In primary cardiac cells, cAMP induces a 6-fold increase in the steady state levels of Kv1.5 transcript. However, in GH3 cells cAMP induces a 5-6-fold decrease in steady state levels of Kv1.5 transcript."
"Upon internalization, Kv1.5 rapidly associated with Rab5-and Rab4-positive endosomes, suggesting that the channel is internalized via a Rab5-dependent pathway and rapidly targeted for recycling to the plasma membrane."
"Upon internalization, Kv1.5 rapidly associated with Rab5-and Rab4-positive endosomes, suggesting that the channel is internalized via a Rab5-dependent pathway and rapidly targeted for recycling to the plasma membrane."
"Indeed, a loss-of-function mutation in KCNA5 associated with AF results in decreased ultrarapid delayed rectifier potassium current ( I Kur ), prolongation of the atrial action potential, and facilitates early afterdepolarizations. xref Recent discoveries have also revealed mechanisms by which mutations in sodium channels may influence AF susceptibility."
"Important issues regarding the safety of I Kur blockers have been raised recently with the finding that loss-of-function mutations in KCNA5 are associated with familial AF. xref Because KCNA5 encodes the α subunit of the I Kur channel, these results suggest that a reduction in I Kur may predispose to the development of AF."
"In accordance, we had shown in differentiated hESC-AMs that COUP-TFII is able to bind to the promoters of atrial specific ion channel genes KCNA5 and KCNJ3 and regulates their expression in hESC derived CMs."
"In accordance, we had shown in differentiated hESC-AMs that COUP-TFII is able to bind to the promoters of atrial-specific ion channel genes KCNA5 and KCNJ3 and regulates their expression in hESC-derived CMs ( xref )."
"In light of the previous evidence, the main goal of this report is to replicate the association of KCNA5 rs10744676 polymorphism with SSc and SSc-related PAH in an independent European population of Caucasian ancestry."
"Upon internalization, Kv1.5 rapidly associated with Rab5-and Rab4-positive endosomes, suggesting that the channel is internalized via a Rab5-dependent pathway and rapidly targeted for recycling to the plasma membrane."
"Upon internalization, Kv1.5 rapidly associated with Rab5-and Rab4-positive endosomes, suggesting that the channel is internalized via a Rab5-dependent pathway and rapidly targeted for recycling to the plasma membrane."
"In accordance, we had shown in differentiated hESC-AMs that COUP-TFII is able to bind to the promoters of atrial specific ion channel genes KCNA5 and KCNJ3 and regulates their expression in hESC derived CMs."
"In accordance, we had shown in differentiated hESC-AMs that COUP-TFII is able to bind to the promoters of atrial-specific ion channel genes KCNA5 and KCNJ3 and regulates their expression in hESC-derived CMs ( xref )."
"Interaction with Kv1.5 of myc-CHIP ∆U was much less than that of myc-CHIP WT ( Fig. 5 B), whereas the interaction with Hsc70 remained unaltered ( Fig. 6 A, right panel)."
"In atrial muscle, Kv1.5 labeling was closely associated with labeling of Cx43 (gap junction protein) and DPI/II (desmosomal protein), whereas in SA node Kv1.5 labeling was closely associated with labeling of DPI/II but not labeling of Cx43 (absent in the SA node) or Cx45 (another gap junction protein present in the SA node)."
"In atrial muscle, Kv1.5 labeling was closely associated with labeling of Cx43 (gap junction protein) and DPI/II (desmosomal protein), whereas in SA node Kv1.5 labeling was closely associated with labeling of DPI/II but not labeling of Cx43 (absent in the SA node) or Cx45 (another gap junction protein present in the SA node)."
"In addition to showing the association of Kv1.5 with cortactin, Radice group used cardiac-specific N- cadherin conditional knockout mice to provide strong evidence for essential roles of N- cadherin in ICD integrity, cardiac conduction & rhythms, and I k,slow1 surface expression [ xref , xref – xref ]."
"It is known that mXinα interacts not only with cortactin ( xref ) but also with p120-catenin ( xref ) and β-catenin ( xref ), suggesting that mXinα may be required for the association of Kv1.5, cortactin, and N-cadherin."
"It has been reported that overexpression of the KCNA5 gene induces accelerated K efflux and increases caspase-3 proteolytic activity, promoting apoptosis [XREF_BIBR]."
"Overexpression of the human KCNA5 gene increases K+ currents (i.e., K+ efflux or loss), accelerates apoptotic volume decrease (AVD), increases caspase-3 activity, and induces apoptosis."
"In atrial muscle, Kv1.5 labeling was closely associated with labeling of Cx43 (gap junction protein) and DPI/II (desmosomal protein), whereas in SA node Kv1.5 labeling was closely associated with labeling of DPI/II but not labeling of Cx43 (absent in the SA node) or Cx45 (another gap junction protein present in the SA node)."
"In atrial muscle, Kv1.5 labeling was closely associated with labeling of Cx43 (gap junction protein) and DPI/II (desmosomal protein), whereas in SA node Kv1.5 labeling was closely associated with labeling of DPI/II but not labeling of Cx43 (absent in the SA node) or Cx45 (another gap junction protein present in the SA node)."
"In addition to showing the association of Kv1.5 with cortactin, Radice group used cardiac-specific N- cadherin conditional knockout mice to provide strong evidence for essential roles of N- cadherin in ICD integrity, cardiac conduction & rhythms, and I k,slow1 surface expression [ xref , xref – xref ]."
"It is known that mXinα interacts not only with cortactin ( xref ) but also with p120-catenin ( xref ) and β-catenin ( xref ), suggesting that mXinα may be required for the association of Kv1.5, cortactin, and N-cadherin."
"Current research indicates that Kv1.5, similar to Kv1.3, is inhibited by 4-AP, TEA, and some new chemicals, such as S0100176 (from Sanofi-Aventis) or diphenyl phosphine oxide-1 (DPO-1) 2."
"Therefore, the ~ 50% decrease in I Kur and Kv1.5 protein levels in AF may reflect a combination of decreased cell surface trafficking and enhanced endocytosis of Kv1.5 leading to channel degradation."
"As noted above, Zn 2+ also causes a concentration and K o + -dependent inhibition of Kv1.5 currents and for that reason its effects on inactivation were also examined."
"Current research indicates that Kv1.5, similar to Kv1.3, is inhibited by 4-AP, TEA, and some new chemicals, such as S0100176 (from Sanofi-Aventis) or diphenyl phosphine oxide-1 (DPO-1) 2."
"With the use of inside-out macropatches, we found that perhexiline inhibited Kv1.5 current in a time- and voltage-dependent manner with an IC50 value of 1.5 x 10(-6) M at +50 mV."
"Sp1 has known sensitivity to oxidative stress and, consistent with this property, Kcna5 promoter activity was suppressed by hydrogen peroxide induced oxidative stress."
"# Ariadne: The transcription of a potassium channel gene, Kv1.5 , is regulated by glucocorticoids and cAMP in both GH3 cells and cardiac myocytes ( 16-18 ). [Expression]"
"In 1 mM Cd 2+ the V 1/2 for the g-V relationship was shifted rightward by 19.5 +/- 1.2 mV.Of the divalent cations we tested for an ability to block Kv1.5, Mn 2+ proved to be the least effective."
"Current research indicates that Kv1.5, similar to Kv1.3, is inhibited by 4-AP, TEA, and some new chemicals, such as S0100176 (from Sanofi-Aventis) or diphenyl phosphine oxide-1 (DPO-1) 2."
"Expression studies in Xenopus oocytes demonstrated that NHERF1 and NHERF2 activate Kv1.5, an effect requiring the C-terminal PDZ-binding motif on Kv1.5."
"Expression studies in Xenopus oocytes demonstrated that NHERF1 and NHERF2 activate Kv1.5, an effect requiring the C-terminal PDZ-binding motif on Kv1.5."
"Benson et al have reported that SENP2 can de-SUMOylate Kv1.5 and lead to a substantial hyperpolarizing shift in the voltage dependence of steady-state inactivation( xref )."
"Inhibition of mitochondrial oxidative phosphorylation with either phenformin or hypoxia was found to result in AMP-activated protein kinase (AMPK)-mediated inhibition of Kv1.5 channels in rat PASMCs."
"Hence, it is possible that Ang II- or oxLDL-induced increase in Kv1.5 may interact with TGF-β/SMAD signaling pathway, especial with SMAD4, which can reduce UCP2 expression, enhance mitochondrial ROS production and promote endothelial injury."
"A nonsense mutation in the pore domain (E375X) and three missense mutations in the C-terminal region of KCNA5 (T527M, A576V, E610K) are associated with autosomal dominant atrial fibrillation susceptibility type 7 (ATFB7; xref )."
"Additionally, our results predict that deterioration of the actin cytoskeleton would disrupt myosin mediated delivery of Kv1.5 to the plasma membrane."
"In fact, the presence of the Kvbeta2.1 subunit impairs the location of Kv1.5 in rafts, and this has been proposed to be the mechanism of how Kv1.5 colocalizes with caveolin in heterologous expression systems that lack Kvbeta expression but does not in native cells and tissues."
"A consistent pattern that emerges from these studies, whether it is the spontaneously occurring conductance collapse in Shaker IR and Kv1.5 mutant channels or the metal ion induced block and conductance collapse in wt Kv1.5, is that inhibition of the conductance loss occurs with low millimolar K o + concentrations and that this inhibition occurs in the absence of a change of the inactivation rate measured during depolarizing pulses."
"In oxLDL induced endothelial cell injury model, we further found that knockdown of KCNA5 gene attenuated, whereas overexpression of KCNA5 gene enhanced oxLDL induced endothelial morphological changes, ROS generation derived from NADPH oxidase and mitochondria, and the protein expression of uncoupling protein 2 (UCP2), a modulator of mitochondria derived ROS production XREF_BIBR, XREF_BIBR."
"Diamide treatment produced a robust, global increase in sulfenic acid modified proteins in the heart (XREF_SUPPLEMENTARY), and importantly, increased sulfenic acid modification to Kv1.5 (XREF_FIG)."
"Moreover, voltage dependent potassium channels are also targeted by miRNAs - KCNA5 as a target of miR-1, KCNQ5 as a target of miR-190 and TASK1 as a target of miR-138."
"Currents through the Kv1.5 H463Q construct decreased by ~ 30% in 5 mM Ni 2+ and, as with the Zn 2+ block of this mutant channel (Kehl et al., 2002), the n H fitted to the concentration dependence of this block was quite small (~ 0.5) suggesting the involvement of a binding site and mechanism of action that is different."
"Silencing Kv1.5 expression in the osteosarcoma cells significantly inhibited the proliferation of osteosarcoma cells, induced cell cycle arrest at G0/G1 phase, and induced cell apoptosis through up-regulation of p21, p27, Bax, Bcl-XL and caspase-3 and down-regulation of cyclins A, cyclins D1, cyclins E, Bcl-2 and Bik."
"Upon internalization, Kv1.5 rapidly associated with Rab5-and Rab4-positive endosomes, suggesting that the channel is internalized via a Rab5-dependent pathway and rapidly targeted for recycling to the plasma membrane."
"In light of the previous evidence, the main goal of this report is to replicate the association of KCNA5 rs10744676 polymorphism with SSc and SSc-related PAH in an independent European population of Caucasian ancestry."
"Hence, it is possible that Ang II- or oxLDL-induced increase in Kv1.5 may interact with TGF-β/SMAD signaling pathway, especial with SMAD4, which can reduce UCP2 expression, enhance mitochondrial ROS production and promote endothelial injury."
"A nonsense mutation in the pore domain (E375X) and three missense mutations in the C-terminal region of KCNA5 (T527M, A576V, E610K) are associated with autosomal dominant atrial fibrillation susceptibility type 7 (ATFB7; xref )."
"This, however, yielded positive and negative results, with on one hand associations of NLRP1 and KCNA5 with PAH, and on the other hand no associations with fibrosis-related MMP genes."
"On the other hand, the epitopes recognized by U1040 are located at the extreme C‐terminus of Xirp2, which may not be required for Xirp2 to interact with Kv1.5 and Nav1.5."
"In accordance, we had shown in differentiated hESC-AMs that COUP-TFII is able to bind to the promoters of atrial-specific ion channel genes KCNA5 and KCNJ3 and regulates their expression in hESC-derived CMs ( xref )."
"We then determined whether PcG proteins interacted with the promoter region of Kcna5 or Kcnab2 and whether changes in PcG protein abundance can result in alteration of outward potassium currents."
"It was recently shown that exposure of neuronal cells to acute hypoxia and glucose deprivation leads to apoptosis and that this ischemia-induced cell death is associated with up-regulation of Kv1.5 expression ( xref )."
"If MK801 and ketamine inhibit Kv1.5, these drugs could be hypothesized to augment 5-HT 2A R signaling by facilitating 5-HT 2A R-mediated Kv1.5 inhibition and E m depolarization."
"These results indicated that Kv1.5 silencing induced G0/G1 arrest in osteosarcoma cells through a mechanism involving the up-regulation of cdk inhibitors p21 and p27."
"The interaction between Kv1.5-FLAG and CHIP was further demonstrated by 72.7% colocalization in the immunofluorescence experiment (supplementary Fig. 1)."
"Coimmunoprecipitation experiments demonstrated a direct interaction between Kv1.5 and the dynein motor complex in both heterologous cells and rat cardiac myocytes, supporting the role of this complex in Kv1.5 trafficking, which required an intact SH3-binding domain in the Kv1.5 N terminus to occur."
"We have delineated a Kv1.5 aminoterminal region of up to 90 amino acids (residues 112-201) that is sufficient for interactions of Kv1.5 alpha and Kv beta 1 subunits."
"To test whether the atrial enriched ion channel genes KCNA5 and KCNJ3 are direct targets of COUP-TFs, we performed ChIP-qPCR assays using day 30 hESC-atrial CMs."
"It was recently shown that exposure of neuronal cells to acute hypoxia and glucose deprivation leads to apoptosis and that this ischemia-induced cell death is associated with up-regulation of Kv1.5 expression ( xref )."
"In contrast to PE, a 48% enhancement of the protein expression of Kv1.5 channel was induced by IGF-1 and this stimulation was specifically blocked by genistein."
"In atrial muscle, Kv1.5 labeling was closely associated with labeling of Cx43 (gap junction protein) and DPI/II (desmosomal protein), whereas in SA node Kv1.5 labeling was closely associated with labeling of DPI/II but not labeling of Cx43 (absent in the SA node) or Cx45 (another gap junction protein present in the SA node)."
"The interaction between Kv1.5-FLAG and CHIP was further demonstrated by 72.7% colocalization in the immunofluorescence experiment (supplementary Fig. 1)."
"The Kv1.5 and Kv2.1 K+-channel alpha subunits are constitutively tyrosine phosphorylated and physically associate with Fyn both in cultured SCs and in the sciatic nerve in vivo."
"Coimmunoprecipitation experiments demonstrated a direct interaction between Kv1.5 and the dynein motor complex in both heterologous cells and rat cardiac myocytes, supporting the role of this complex in Kv1.5 trafficking, which required an intact SH3-binding domain in the Kv1.5 N terminus to occur."
"We have delineated a Kv1.5 aminoterminal region of up to 90 amino acids (residues 112-201) that is sufficient for interactions of Kv1.5 alpha and Kv beta 1 subunits."
"Using inhibitors of PDGF-activated pathways, we found that PDGF-induced upregulation of Kv1.5 and I(K) density involves Src family tyrosine kinases, sphingosine kinase, and intracellular Ca(2+) but not ERK1/2 or phosphatidylinositol 3-kinase pathways."
"In both cases, Rab11 mediates cargo protein recycling back to the plasma membrane, and it is not known whether the IL-8 receptors or Kv1.5 directly interact with Rab11."
"It is known that mXinα interacts not only with cortactin ( xref ) but also with p120-catenin ( xref ) and β-catenin ( xref ), suggesting that mXinα may be required for the association of Kv1.5, cortactin, and N-cadherin."
"Because C-type inactivated Shaker IR (Starkus et al., 1997) and Kv1.5 (Wang et al., 2000a) channels are able to conduct Na + ions, the current view is that the conformational change at the outer pore mouth involves an incomplete constriction rather than a complete collapse."