Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents

Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Adrien eMoreau [verfasserIn] Pascal eGosselin-Badaroudine [verfasserIn] Mohamed eBoutjdir [verfasserIn] Mohamed eChahine [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2015

Schlagwörter:	Voltage sensor arrhythmias SCN5A dilated cardiomyopathy gating pore current

Übergeordnetes Werk:	In: Frontiers in Pharmacology - Frontiers Media S.A., 2010, 6(2015)
Übergeordnetes Werk:	volume:6 ; year:2015

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fphar.2015.00301

Katalog-ID:	DOAJ074937782

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520			\|a Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD.
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allfields	10.3389/fphar.2015.00301 doi (DE-627)DOAJ074937782 (DE-599)DOAJ455df5995d094f79a3d6ff5ccb195dd7 DE-627 ger DE-627 rakwb eng RM1-950 Adrien eMoreau verfasserin aut Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD. Voltage sensor arrhythmias SCN5A dilated cardiomyopathy gating pore current Therapeutics. Pharmacology Pascal eGosselin-Badaroudine verfasserin aut Mohamed eBoutjdir verfasserin aut Mohamed eChahine verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 6(2015) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:6 year:2015 https://doi.org/10.3389/fphar.2015.00301 kostenfrei https://doaj.org/article/455df5995d094f79a3d6ff5ccb195dd7 kostenfrei http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00301/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2015
spelling	10.3389/fphar.2015.00301 doi (DE-627)DOAJ074937782 (DE-599)DOAJ455df5995d094f79a3d6ff5ccb195dd7 DE-627 ger DE-627 rakwb eng RM1-950 Adrien eMoreau verfasserin aut Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD. Voltage sensor arrhythmias SCN5A dilated cardiomyopathy gating pore current Therapeutics. Pharmacology Pascal eGosselin-Badaroudine verfasserin aut Mohamed eBoutjdir verfasserin aut Mohamed eChahine verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 6(2015) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:6 year:2015 https://doi.org/10.3389/fphar.2015.00301 kostenfrei https://doaj.org/article/455df5995d094f79a3d6ff5ccb195dd7 kostenfrei http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00301/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2015
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allfieldsGer	10.3389/fphar.2015.00301 doi (DE-627)DOAJ074937782 (DE-599)DOAJ455df5995d094f79a3d6ff5ccb195dd7 DE-627 ger DE-627 rakwb eng RM1-950 Adrien eMoreau verfasserin aut Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD. Voltage sensor arrhythmias SCN5A dilated cardiomyopathy gating pore current Therapeutics. Pharmacology Pascal eGosselin-Badaroudine verfasserin aut Mohamed eBoutjdir verfasserin aut Mohamed eChahine verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 6(2015) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:6 year:2015 https://doi.org/10.3389/fphar.2015.00301 kostenfrei https://doaj.org/article/455df5995d094f79a3d6ff5ccb195dd7 kostenfrei http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00301/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2015
allfieldsSound	10.3389/fphar.2015.00301 doi (DE-627)DOAJ074937782 (DE-599)DOAJ455df5995d094f79a3d6ff5ccb195dd7 DE-627 ger DE-627 rakwb eng RM1-950 Adrien eMoreau verfasserin aut Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD. Voltage sensor arrhythmias SCN5A dilated cardiomyopathy gating pore current Therapeutics. Pharmacology Pascal eGosselin-Badaroudine verfasserin aut Mohamed eBoutjdir verfasserin aut Mohamed eChahine verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 6(2015) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:6 year:2015 https://doi.org/10.3389/fphar.2015.00301 kostenfrei https://doaj.org/article/455df5995d094f79a3d6ff5ccb195dd7 kostenfrei http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00301/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 6 2015
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source	In Frontiers in Pharmacology 6(2015) volume:6 year:2015
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topic_facet	Voltage sensor arrhythmias SCN5A dilated cardiomyopathy gating pore current Therapeutics. Pharmacology
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container_title	Frontiers in Pharmacology
authorswithroles_txt_mv	Adrien eMoreau @@aut@@ Pascal eGosselin-Badaroudine @@aut@@ Mohamed eBoutjdir @@aut@@ Mohamed eChahine @@aut@@
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callnumber-first	R - Medicine
author	Adrien eMoreau
spellingShingle	Adrien eMoreau misc RM1-950 misc Voltage sensor misc arrhythmias misc SCN5A misc dilated cardiomyopathy misc gating pore current misc Therapeutics. Pharmacology Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents
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topic_title	RM1-950 Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents Voltage sensor arrhythmias SCN5A dilated cardiomyopathy gating pore current
topic	misc RM1-950 misc Voltage sensor misc arrhythmias misc SCN5A misc dilated cardiomyopathy misc gating pore current misc Therapeutics. Pharmacology
topic_unstemmed	misc RM1-950 misc Voltage sensor misc arrhythmias misc SCN5A misc dilated cardiomyopathy misc gating pore current misc Therapeutics. Pharmacology
topic_browse	misc RM1-950 misc Voltage sensor misc arrhythmias misc SCN5A misc dilated cardiomyopathy misc gating pore current misc Therapeutics. Pharmacology
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title	Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents
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title_full	Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents
author_sort	Adrien eMoreau
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title_sort	mutations in the voltage sensors of domains i and ii of nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents
callnumber	RM1-950
title_auth	Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents
abstract	Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD.
abstractGer	Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD.
abstract_unstemmed	Voltage gated sodium channels (Nav) are transmembrane proteins responsible for action potential initiation. Mutations mainly located in the voltage sensor domain (VSD) of Nav1.5, the cardiac sodium channel, have been associated with the development of arrhythmias combined with dilated cardiomyopathy. Gating pore currents have been observed with three unrelated mutations associated with similar clinical phenotypes. However, gating pores have never been associated with mutations outside the first domain of Nav1.5.The aim of this study was to explore the possibility that gating pore currents might be caused by the Nav1.5 R225P and R814W mutations (R3, S4 in DI and DII, respectively), which are associated with rhythm disturbances and dilated cardiomyopathy.Nav1.5 WT and mutant channels were transiently expressed in tsA201 cells. The biophysical properties of the alpha pore currents and the presence of gating pore currents were investigated using the patch-clamp technique.We confirmed the previously reported gain of function of the alpha pores of the mutant channels, which mainly consisted of increased window currents mostly caused by shifts in the voltage dependence of activation. We also observed gating pore currents associated with the R225P and R814W mutations. This novel permeation pathway was open under depolarized conditions and remained temporarily open at hyperpolarized potentials after depolarization periods.Gating pore currents could represent a molecular basis for the development of uncommon electrical abnormalities and changes in cardiac morphology. We propose that this biophysical defect be routinely evaluated in the case of Nav1.5 mutations on the VSD.
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title_short	Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents
url	https://doi.org/10.3389/fphar.2015.00301 https://doaj.org/article/455df5995d094f79a3d6ff5ccb195dd7 http://journal.frontiersin.org/Journal/10.3389/fphar.2015.00301/full https://doaj.org/toc/1663-9812
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up_date	2024-07-04T01:11:51.908Z
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Mutations in the voltage sensors of domains I and II of Nav1.5 that are associated with arrhythmias and dilated cardiomyopathy generate gating pore currents

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