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The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants
Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affect...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Research Foundation
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108560/ https://www.ncbi.nlm.nih.gov/pubmed/21687499 http://dx.doi.org/10.3389/fphar.2011.00002 |
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author | Miceli, Francesco Soldovieri, Maria Virginia Iannotti, Fabio Arturo Barrese, Vincenzo Ambrosino, Paolo Martire, Maria Cilio, Maria Roberta Taglialatela, Maurizio |
author_facet | Miceli, Francesco Soldovieri, Maria Virginia Iannotti, Fabio Arturo Barrese, Vincenzo Ambrosino, Paolo Martire, Maria Cilio, Maria Roberta Taglialatela, Maurizio |
author_sort | Miceli, Francesco |
collection | PubMed |
description | Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitability (epilepsy, pain), or skeletal muscle contraction (periodic paralysis). Moreover, gating changes appear as the main molecular mechanism by which several natural toxins from a variety of species affect ion channel function. In this work, we describe the pathophysiological and pharmacological relevance of the gating process in voltage-gated K(+) channels encoded by the K(v)7 gene family. After reviewing the current knowledge on the molecular mechanisms and on the structural models of voltage-dependent gating in VGICs, we describe the physiological relevance of these channels, with particular emphasis on those formed by K(v)7.2–K(v)7.5 subunits having a well-established role in controlling neuronal excitability in humans. In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans. Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels. Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability. |
format | Online Article Text |
id | pubmed-3108560 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Frontiers Research Foundation |
record_format | MEDLINE/PubMed |
spelling | pubmed-31085602011-06-16 The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants Miceli, Francesco Soldovieri, Maria Virginia Iannotti, Fabio Arturo Barrese, Vincenzo Ambrosino, Paolo Martire, Maria Cilio, Maria Roberta Taglialatela, Maurizio Front Pharmacol Neuroscience Understanding the molecular mechanisms underlying voltage-dependent gating in voltage-gated ion channels (VGICs) has been a major effort over the last decades. In recent years, changes in the gating process have emerged as common denominators for several genetically determined channelopathies affecting heart rhythm (arrhythmias), neuronal excitability (epilepsy, pain), or skeletal muscle contraction (periodic paralysis). Moreover, gating changes appear as the main molecular mechanism by which several natural toxins from a variety of species affect ion channel function. In this work, we describe the pathophysiological and pharmacological relevance of the gating process in voltage-gated K(+) channels encoded by the K(v)7 gene family. After reviewing the current knowledge on the molecular mechanisms and on the structural models of voltage-dependent gating in VGICs, we describe the physiological relevance of these channels, with particular emphasis on those formed by K(v)7.2–K(v)7.5 subunits having a well-established role in controlling neuronal excitability in humans. In fact, genetically determined alterations in K(v)7.2 and K(v)7.3 genes are responsible for benign familial neonatal convulsions, a rare seizure disorder affecting newborns, and the pharmacological activation of K(v)7.2/3 channels can exert antiepileptic activity in humans. Both mutation-triggered channel dysfunction and drug-induced channel activation can occur by impeding or facilitating, respectively, channel sensitivity to membrane voltage and can affect overlapping molecular sites within the voltage-sensing domain of these channels. Thus, understanding the molecular steps involved in voltage-sensing in K(v)7 channels will allow to better define the pathogenesis of rare human epilepsy, and to design innovative pharmacological strategies for the treatment of epilepsies and, possibly, other human diseases characterized by neuronal hyperexcitability. Frontiers Research Foundation 2011-02-01 /pmc/articles/PMC3108560/ /pubmed/21687499 http://dx.doi.org/10.3389/fphar.2011.00002 Text en Copyright © 2011 Miceli, Soldovieri, Iannotti, Barrese, Ambrosino, Martire, Cilio and Taglialatela. http://www.frontiersin.org/licenseagreement This is an open-access article subject to an exclusive license agreement between the authors and Frontiers Media SA, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited. |
spellingShingle | Neuroscience Miceli, Francesco Soldovieri, Maria Virginia Iannotti, Fabio Arturo Barrese, Vincenzo Ambrosino, Paolo Martire, Maria Cilio, Maria Roberta Taglialatela, Maurizio The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants |
title | The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants |
title_full | The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants |
title_fullStr | The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants |
title_full_unstemmed | The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants |
title_short | The Voltage-Sensing Domain of K(v)7.2 Channels as a Molecular Target for Epilepsy-Causing Mutations and Anticonvulsants |
title_sort | voltage-sensing domain of k(v)7.2 channels as a molecular target for epilepsy-causing mutations and anticonvulsants |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108560/ https://www.ncbi.nlm.nih.gov/pubmed/21687499 http://dx.doi.org/10.3389/fphar.2011.00002 |
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