"Seizures and ataxia responded poorly to antiepileptic drugs (topiramate, oxcarbazepine, valproic acid, bromide), including acetazolamide (known to be effective in EA1 caused by mutations in KCNA1 18)."
"EA1 is caused by mutations in KCNA1 gene located on chromosome 12p13 (MIM 160120), which encodes Kv1.1, a voltage gated potassium channel [XREF_BIBR]."
"Episodic ataxia type 1 (EA1) is caused by mutations in the KCNA1 gene encoding the fast potassium channel Kv1.1 and is characterized clinically by brief episodes of ataxia and continuous and spontaneous motor unit activity."
"Episodic ataxia type 1 (EA-1) is caused by missense mutations in the potassium channel gene KCNA1, whereas episodic ataxia type 2 (EA-2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A."
"Several other EA syndromes have been described; mutations in KCNA1 - the gene that encodes the K V 1.1 potassium channel - underlie EA1, which is characterised by brief attacks of ataxia (lasting minutes) with interictal myokymia [XREF_BIBR - XREF_BIBR]."
"Mutations in a potassium channel gene (KCNA1) located on chromosome 12p13 underlie EA1, and in a voltage dependent calcium channel gene (CACNA1A) located on chromosome 19p13 can lead to EA2."
"To date, eight types of EA have been described; the dominant forms are EA1 (OMIM, 160120) and EA2 (OMIM, 108500), caused by mutations in KCNA1 (OMIM, 176260) and CACNA1A (OMIM, 601011), respectively."
"Heterozygous mutations of KCNA1, the gene encoding potassium channel Kv1.1 subunits, cause episodic ataxia type 1 (EA1), which is characterized by paroxysmal cerebellar incoordination and interictal myokymia."
"The functional consequences of human KCNA1 mutations causing typical myokymia and EA1 have been reported [XREF_BIBR], much less is known about the functional consequences of mutations causing unusual KCNA1 associated phenotypes."
"Episodic ataxia type 1 (EA1) is an autosomal dominant and sporadic neurological disorder characterized by frequent, short-lasting attacks of uncoordinated movements and involuntary, repetitive muscle contraction (myokymia); genetic analyses indicate that EA1 is associated with mutations in the KCNA1 gene on chromosome 12p that encodes the human Kv1.1 α subunit xref xref xref xref xref ."
"The result that HuD only binds Kv1.1 mRNA in neurons treated with rapamycin supports a role for HuD in promoting Kv1.1 mRNA translation when mTORC1 is inhibited."
"If HuD binding to Kv1.1 mRNA requires the degradation of high affinity targets such as CaMKIIα mRNA, overexpression of CaMKIIα mRNA containing several HuD binding sites may affect the dendritic expression of Kv1.1 protein."
"HuD binding to Kv1.1 occurs as a result of the degradation of other high-affinity targets of HuD, such as CamKIIα, GAP-43, and Homer 1a, when mTOR is inactive."
"To verify the predicted binding of HuD to Kv1.1 mRNA, coimmunoprecipitation of transfected HEK293T cells was used to assess whether HuD binds directly to Kv1.1 mRNA."
"Here, we report the identification of an miRNA, miR-129, and an RNA-binding protein, HuD, both of which reversibly bind Kv1.1 mRNA when mTORC1 kinase is active and inactive, respectively."
"Because rbk1 mutants display similar phenotypes to mpk1 , and because MPK1 phosphorylates RBK1, we hypothesize that RBK1 may act in the MKK3 • MPK1 signaling cascade to influence auxin-responsive cell expansion."
"This data suggests that MPK1 phosphorylates RBK1, but RBK1 is unable to phosphorylate MPK1 T191A/Y193A , either because MPK1 is not a substrate of RBK1 or because RBK1 specifically phosphorylates the T191 or Y193 residues of MPK1."
"Because mpk1 and rbk1 mutants display similar phenotypes ( xref and xref ) and because MPK1 may interact with RBK1, we hypothesized that RBK1 serves as an MPK1 phosphorylation target."
"We found that RBK1 directly phosphorylates ROP4 and ROP6, supporting the possibility that RBK1 effects on auxin-responsive cell expansion are mediated through phosphorylation-dependent modulation of ROP activity."
"We found that RBK1 directly phosphorylates ROP4 and ROP6, consistent with the possibility that RBK1 effects on auxin-responsive cell expansion are mediated through phosphorylation-dependent modulation of ROP activity."
"Here, we report the identification of an miRNA, miR-129, and an RNA-binding protein, HuD, both of which reversibly bind Kv1.1 mRNA when mTORC1 kinase is active and inactive, respectively."
"Heterozygous mutations of KCNA1, the gene encoding potassium channel Kv1.1 subunits, cause episodic ataxia type 1 (EA1), which is characterized by paroxysmal cerebellar incoordination and interictal myokymia."
"Here, we report the identification of an miRNA, miR-129, and an RNA-binding protein, HuD, both of which reversibly bind Kv1.1 mRNA when mTORC1 kinase is active and inactive, respectively."
"However, we do not know how MPK1-mediated phosphorylation of RBK1 affects its activity, nor do we understand how ROP protein phosphorylation by RBK1 affects ROP activity."
"Because loss of RBK1 function results in increased auxin responsiveness ( xref ) and loss of ROP function leads to decreased auxin responsiveness ( xref ; xref ; xref ; xref ), we hypothesize that ROP phosphorylation by RBK1 could negatively impact ROP function ( xref )."
"In this study, we identified MKK3 • MPK1 • RBK1 as a potential kinase cascade that terminates in ROP protein phosphorylation. xref suggested that RBK1 may act downstream of ROP proteins, because they did not observe phosphorylation of ROP proteins by RBK1 in a kinase assay."
"Browne D, Gancher S,
Nutt J, Brunt E, Smith E, Kramer P, Litt M: Episodic
ataxia/myokymia syndrome is associated with point mutations in the
human potassium channel gene, KCNA1."
"This manuscript showed that
mutations in the voltage-dependent delayed rectifier potassium channel
gene, KCNA1, associated with episodic ataxia cause loss, alteration
and dominant-negative suppression of channel function."
"Episodic ataxia type 1 (EA1) is caused by mutations in the KCNA1 gene encoding the fast potassium channel Kv1.1 and is characterized clinically by brief episodes of ataxia and continuous and spontaneous motor unit activity."
"Browne D, Gancher S,
Nutt J, Brunt E, Smith E, Kramer P, Litt M: Episodic
ataxia/myokymia syndrome is associated with point mutations in the
human potassium channel gene, KCNA1."
"This manuscript showed that
mutations in the voltage-dependent delayed rectifier potassium channel
gene, KCNA1, associated with episodic ataxia cause loss, alteration
and dominant-negative suppression of channel function."
"Recognition of interactions of kappa-Hefutoxin1 with the voltage-gated potassium channels, Kv1.1, Kv1.2, and Kv1.3, was studied by 3D-Dock software package."
"We then carried out a rescue experiment by overexpressing KCNA1, the data indicated that KCNA1 significantly abolished the invasion-inhibitory effect of miR-125b."
"We further assessed whether KCNA1 participated in the invasion-inhibitory effect of miR-125b in human trophoblast cells via co-transfection of miR-125b and KCNA1 overexpression vector, we found that overexpression of KCNA1 gene significantly abolished the invasion-inhibitory effect of miR-125b."
"We found that RBK1 directly phosphorylates ROP4 and ROP6, consistent with the possibility that RBK1 effects on auxin-responsive cell expansion are mediated through phosphorylation-dependent modulation of ROP activity."
"We found that RBK1 directly phosphorylates ROP4 and ROP6, supporting the possibility that RBK1 effects on auxin-responsive cell expansion are mediated through phosphorylation-dependent modulation of ROP activity."
"Binding of ANK3 to Kv1.1 resulted in a reduction of the ensemble current, most likely by affecting the channel open probability (P 0 ) rather than influencing its voltage dependence or the number of channels at the plasma membrane."
"29 Although ankyrin-binding motifs are not present in the Kv1.1 channel, we confirmed the interaction by co-immunoprecipitations using the GST-tagged C-terminus of Kv1.1 and hemagglutinin-tagged ANK3 transiently expressed in HEK293 cell lysates."
"Recognition of interactions of kappa-Hefutoxin1 with the voltage-gated potassium channels, Kv1.1, Kv1.2, and Kv1.3, was studied by 3D-Dock software package."
"We demonstrate that fluorescently labeled agitoxin 2 binds specifically to high-affinity and lower-affinity sites of KcsA-Kv1.3 and KcsA-Kv1.1, respectively, at the membrane of spheroplasts."
"We further show that the N terminus of Kv1.1 binds brain synaptosomal and recombinant syntaxin 1A and concomitantly binds beta(1)gamma(2); the binding of beta(1)gamma(2) enhances that of syntaxin 1A. Taken together, we suggest a mechanism whereby syntaxin and G protein betagamma subunits interact concomitantly with a Kv channel to regulate its inactivation."
"Studies have shown that Syntaxin 1A interacts with both Kv2.1 and Kv1.1 and modulates the firing frequency of the pre-synaptic membrane ( xref ; xref )."
"As described previously [ xref , xref ], ShK inhibited Kv1.3 and Kv1.1 channels with similar potencies (IC 50 of 9 ± 2 pM for Kv1.3 and 23 ± 3 pM for Kv1.1)."
"LGI1 also indirectly binds Kv1.1 VGKC (voltage-gated potassium channels), which is a major constituent of presynaptic A-type channels that modulate synaptic transmission in CNS neurons (Schulte et al., xref )."
"Episodic ataxia type 1, an autosomal dominant neurological disorder, is caused by a mutation of the KCNA1 gene encoding the voltage gated K + channel K V 1.1, which substitutes valine for leucine at position 408 [XREF_BIBR]."
"Because mpk1 and rbk1 mutants display similar phenotypes ( xref and xref ) and because MPK1 may interact with RBK1, we hypothesized that RBK1 serves as an MPK1 phosphorylation target."
"We demonstrate that fluorescently labeled agitoxin 2 binds specifically to high-affinity and lower-affinity sites of KcsA-Kv1.3 and KcsA-Kv1.1, respectively, at the membrane of spheroplasts."
"We further show that the N terminus of Kv1.1 binds brain synaptosomal and recombinant syntaxin 1A and concomitantly binds beta(1)gamma(2); the binding of beta(1)gamma(2) enhances that of syntaxin 1A. Taken together, we suggest a mechanism whereby syntaxin and G protein betagamma subunits interact concomitantly with a Kv channel to regulate its inactivation."
"Studies have shown that Syntaxin 1A interacts with both Kv2.1 and Kv1.1 and modulates the firing frequency of the pre-synaptic membrane ( xref ; xref )."
"Group III pre-treated with AEMK and Group V which received AEMK after RIR, showed significant decrease in MPO activity over the preventive control (II) and curative control (IV) groups indicating that the AEMK had inhibited the neutrophil infiltration ( P < 0.05) [ xref ]."
"LGI1 also indirectly binds Kv1.1 VGKC (voltage-gated potassium channels), which is a major constituent of presynaptic A-type channels that modulate synaptic transmission in CNS neurons (Schulte et al., xref )."
"When NMDARs are present and active, Gadd45b is expressed and the Kcna1 promoter is demethylated, allowing Kv1.1 expression and decreased neuronal excitability."
"These studies provide evidence that pathological KCNA1 mutations lead to a loss-of-function (LOF) of Kv1.1 by various mechanisms [XREF_BIBR, XREF_BIBR]."
"To date, eight types of EA have been described; the dominant forms are EA1 (OMIM, 160120) and EA2 (OMIM, 108500), caused by mutations in KCNA1 (OMIM, 176260) and CACNA1A (OMIM, 601011), respectively."
"AnmTX Cj 3a-1 is homologous to the APEKTx1 toxin from the venom of the sea anemone Anthopleura elegantissima, which inhibits serine proteinases (for example, trypsin, with K d = 124nM) and selectively (and reversibly) inhibits the mammalian potassium channels rK v 1.1 and KCNA1 (IC 50 0.9 nM) 33."
"Caspr2 is a member of the neurexin superfamily that colocalizes and associates with Kv1.1, Kv1.2, and their cytoplasmic Kvβ2 subunit at the juxtaparanodal region ( xref )."
"In voltage-clamp experiments, dendrotoxin-K (DTX-K), a Kv1.1-specific inhibitor, significantly reduced peak outward K + currents in wildtype (WT) atrial cells but not Kcna1 -/- cells, demonstrating an important contribution by Kv1.1-containing channels to mouse atrial repolarizing currents."
"It is known that TEA (tetraethylammonium) inhibits Kv1.1 channels largely due to binding a critical tyrosine (Tyr379) in the pore, whereas Val381 at the equivalent location in Kv1.2 makes it insensitive."
"Among 77 targets, 19 are relevant to CVD such as protein beta-2 adrenergic receptor related with disease myocardial ischemia; potassium voltage-gated channel and sodium channel protein associated with arrhythmia; 5-hydroxytryptamine 2A receptor related with thrombosis, which clarifies the herbal cardiovascular activities such as anti-ischemia, anti-arrhythmic, and antithrombotic."
"In this sense, it has been proposed that interactions of the Kv1.1T1 domain with the more distal N-terminal structures play an important role in defining the strength of the ball-triggered N-type inactivation (Baker et al., xref ) and it has also been recognized that ball interaction(s) with the T1 domain and the S4–S5 linker seem to be crucial for proper development of the fast/N-type inactivation (Isacoff et al., xref ; Holmgren et al., xref ; Baker et al., xref )."
"Similarly, RBK1 transcript is upregulated in response to Phytophthora infestans and Botrytis cinerea infections ( xref ), suggesting that RBK1, and perhapsROP phosphorylation, may have multiple roles in plant growth and stress response."
"Both MECP2_e1 and MECP2_e2 up-regulated GABRA2 (18-fold and three-fold increase, respectively), KCNA1 (seven-fold and three-fold increase, respectively) and FOXG1 (six-fold and three-fold increase, respectively)."
"Both MECP2_e1 and MECP2_e2 up-regulated GABRA2 (18-fold and three-fold increase, respectively), KCNA1 (seven-fold and three-fold increase, respectively) and FOXG1 (six-fold and three-fold increase, respectively)."
"Tau reduction decreased Kcna1 (-/-) video-EEG recorded seizure frequency and duration as well as normalized Kcna1 (-/-) hippocampal network hyperexcitability in vitro."
"Eukaryotic Linear Motif analysis ( xref ) identified a predicted D-domain and multiple predicted phosphorylation sites in the RBK1 protein, consistent with the possibility that RBK1 interacts with a MAP kinase."
"suggested that Zn 2+ inhibition of Kv1.1-containing channels, combined with the intrinsic loss of channel function, caused by the KCNA1 mutations, would exacerbate EA1 symptoms."
"Motor coordination was altered in KI exposed male progeny, at the cerebellar level we observed a decrease of mRNA expression of DCX (-42%) and RC3 (-85%), on the other hand at the cortical level mRNA expression of MBP (+71%), MOBP (+90%) and Kcna1 (+42%) was increased."
"Caspr2 is a member of the neurexin superfamily that colocalizes and associates with Kv1.1, Kv1.2, and their cytoplasmic Kvβ2 subunit at the juxtaparanodal region ( xref )."
"This network reveals five putative direct targets : CACNA1C (Calcium channel) target of miR-149-5p; GJA5 (Gap Junction protein, alpha 5), RNF207 (Ring finger protein 207) and KCNA1 (potassium voltage gated channel shaker related subfamily, member 1) targets of miR-145-5p; KCNA1 which is also a miR-21-5p target; and finally, SLC18A2 (Solute carrier family 18 member 2) target of miR-142-5p."
"Thus Kv1.1 inhibited high cell surface expression and partially retained the heteromer in the endoplasmic reticulum, whereas Kv1.4 stimulated trans-Golgi glycosylation."
"Mutations in KCNA1 (Kv1.1) cause Episodic Ataxia, Type 1 (OMIM 160120), and those in KCND3 (Kv4.3) cause the very rare Spinocerebellar Ataxia 19 (SCA19; OMIM 607346)."
"Among 77 targets, 19 are relevant to CVD such as protein beta-2 adrenergic receptor related with disease myocardial ischemia; potassium voltage-gated channel and sodium channel protein associated with arrhythmia; 5-hydroxytryptamine 2A receptor related with thrombosis, which clarifies the herbal cardiovascular activities such as anti-ischemia, anti-arrhythmic, and antithrombotic."
"In this sense, it has been proposed that interactions of the Kv1.1T1 domain with the more distal N-terminal structures play an important role in defining the strength of the ball-triggered N-type inactivation (Baker et al., xref ) and it has also been recognized that ball interaction(s) with the T1 domain and the S4–S5 linker seem to be crucial for proper development of the fast/N-type inactivation (Isacoff et al., xref ; Holmgren et al., xref ; Baker et al., xref )."
"Mutations in KCNA1 (Kv1.1) cause Episodic Ataxia, Type 1 (OMIM 160120), and those in KCND3 (Kv4.3) cause the very rare Spinocerebellar Ataxia 19 (SCA19; OMIM 607346)."
"Since KCNA1 KO mice also have disrupted rest activity cycles, but unlike BMAL1 KO mice, have robust diurnal rhythms of seizures, these studies may point toward potential mechanisms dissociating circadian effects from sleep and wake effects."
"Mutations in KCNA1 (Kv1.1) cause Episodic Ataxia, Type 1 (OMIM 160120), and those in KCND3 (Kv4.3) cause the very rare Spinocerebellar Ataxia 19 (SCA19; OMIM 607346)."
"However, previous work demonstrated that a c- myc epitope-tagged form of the Xenopus WΔFKv1.1 mutant is not retained in a perinuclear region ( Ribera, 1996 ), consistent with export from the endoplasmic reticulum."
"Eukaryotic Linear Motif analysis ( xref ) identified a predicted D-domain and multiple predicted phosphorylation sites in the RBK1 protein, consistent with the possibility that RBK1 interacts with a MAP kinase."
"Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2."
"Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human potassium channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2."
"Studies have shown that Syntaxin 1A interacts with both Kv2.1 and Kv1.1 and modulates the firing frequency of the pre-synaptic membrane ( xref ; xref )."
"We demonstrate that fluorescently labeled agitoxin 2 binds specifically to high-affinity and lower-affinity sites of KcsA-Kv1.3 and KcsA-Kv1.1, respectively, at the membrane of spheroplasts."
"The potentials of mean force of the wild-type and mutant OSK1 bound to Kv1.1-Kv1.3 channels are constructed using molecular dynamics, and the half-maximal inhibitory concentration (IC(50)) of each toxin-channel complex is computed."
"Recognition of interactions of kappa-Hefutoxin1 with the voltage-gated potassium channels, Kv1.1, Kv1.2, and Kv1.3, was studied by 3D-Dock software package."
"In this study, by means of the Brownian dynamics (BD) method ( Ermak and McCammon, 1978 ), the association of MTX (all of the 35 available structures in the Protein Data Bank; 1TXM) with Kv1.1, Kv1.2, and Kv1.3 was simulated."
"EA 1 is caused by mutations in the potassium channel gene KCNA1 on chromosome 12p13, EA 2 by mutations in the calcium channel gene CACNA1A gene on chromosome 19p13, and EA 5 by mutations in the calcium channel gene CACNB4 & beta on chromosome 2q22-q23."
"Episodic ataxia type 1, an autosomal dominant neurological disorder, is caused by a mutation of the KCNA1 gene encoding the voltage gated K + channel K V 1.1, which substitutes valine for leucine at position 408 [XREF_BIBR]."
"Thus, the KCNA1 CNV is likely a key contributor to both the EE and SUDEP phenotypes, especially given the strong association between missense mutations in the PVP motif and severe forms of epilepsy and intellectual disability."
"The single coding de novo CNV, confirmed by qPCR was at the 3′ end of exon 2 in KCNA1 (FIGURE 2A, B, C) , a gene encoding the Kv1.1 pore forming alpha subunit whose loss of function causes severe epilepsy and SUDEP in animal models xref (FIGURE 2C)."
"Single channel recording results suggest the possibility that Aβ suppression of Kv1.1 also involves direct protein–protein interaction of Aβ with Kv1.1 channel subunits."
"These results indicate that KCNE4 proteins somehow interact with Kv1.1- and Kv1.3-subunits present in the heteromeric complexes and thereby modulate the entire Kv1 channel complex."
"A complete random assembly of Kv1.1- and Kv1.2-subunits into functional channels would imply that 6.25% of all channels should be homomeric Kv1.1, another 6.25% homomeric Kv1.2 channels, whereas the remaining complexes should consist of heteromeric Kv1.1/1.2 channels in different stoichiometry."
"Here, we report the identification of an miRNA, miR-129, and an RNA-binding protein, HuD, both of which reversibly bind Kv1.1 mRNA when mTORC1 kinase is active and inactive, respectively."
"In voltage-clamp experiments, dendrotoxin-K (DTX-K), a Kv1.1-specific inhibitor, significantly reduced peak outward K + currents in wildtype (WT) atrial cells but not Kcna1 -/- cells, demonstrating an important contribution by Kv1.1-containing channels to mouse atrial repolarizing currents."
"Contactin-2 expressed on Schwann cells and oligodendroglia interacts with the transmembrane proteinCaspR2 and Contactin-2 on the axonal membrane to maintain the voltage-gated potassium channelsKv1.1 and Kv1.2 in juxtaparanodes of myelinated axons ( xref ; xref )."
"EZH2 is essential for DNMTs to bind to the EZH2-target promoters such as MYT1 , KCNA1 and cannabinoid receptor 1 ( CNR1 ), and silences expression of these genes. xref Imatinib increased levels of both EZH2 and DNMT3A in leukemia cells ( xref ), which probably caused global epigenetic aberrations and downregulated the expression of important genes involved in regulation of cell growth, apoptosis and drug metabolism, which could relate to acquisition of drug resistance."
"Episodic ataxia type 1 (EA1) is an autosomal dominant and sporadic neurological disorder characterized by frequent, short-lasting attacks of uncoordinated movements and involuntary, repetitive muscle contraction (myokymia); genetic analyses indicate that EA1 is associated with mutations in the KCNA1 gene on chromosome 12p that encodes the human Kv1.1 α subunit xref xref xref xref xref ."
"This manuscript showed that
mutations in the voltage-dependent delayed rectifier potassium channel
gene, KCNA1, associated with episodic ataxia cause loss, alteration
and dominant-negative suppression of channel function."
"When given atropine alone to selectively inhibit the parasympathetic branch, AV blocks in Kcna1 -/- mice were almost completely ameliorated (P = 0.0016), whereas blocking sympathetic activity alone with propranolol had no significant effect (P = 0.39; XREF_FIG)."
"The single coding de novo CNV, confirmed by qPCR was at the 3′ end of exon 2 in KCNA1 (FIGURE 2A, B, C) , a gene encoding the Kv1.1 pore forming alpha subunit whose loss of function causes severe epilepsy and SUDEP in animal models xref (FIGURE 2C)."
"Single channel recording results suggest the possibility that Aβ suppression of Kv1.1 also involves direct protein–protein interaction of Aβ with Kv1.1 channel subunits."
"29 Although ankyrin-binding motifs are not present in the Kv1.1 channel, we confirmed the interaction by co-immunoprecipitations using the GST-tagged C-terminus of Kv1.1 and hemagglutinin-tagged ANK3 transiently expressed in HEK293 cell lysates."
"Among these, consistent interactions relevant to the observed yeast tolerance and detoxification included interactions of HXK1 with ZWF1, ALD4, ALD6, ADH6 , and RBK1; HXK2 with RBK1, SFA1, TDH3 , and PDC6 ; and GLK1 with TDH1 and ADH7 ."
"Potassium two pore domain channel subfamily K member 9 is involved in the oncogenesis of OC, although its prominent expression is paradoxically associated with better survival ( xref ); potassium voltage-gated channelsubfamily H (KCNH) member 1 and KCNH member 2 (KCNH2) expression is associated with poor prognosis ( xref , xref ), and KCNH2 channel activity is associated with tumor drug resistance ( xref )."
"Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamilymember 1 ( KCNQ1 ) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS)."