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      Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies

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          Abstract

          Voltage-gated sodium channels (VGSC) are multi-molecular protein complexes expressed in both excitable and non-excitable cells. They are primarily formed by a pore-forming multi-spanning integral membrane glycoprotein (α-subunit) that can be associated with one or more regulatory β-subunits. The latter are single-span integral membrane proteins that modulate the sodium current ( I Na) and can also function as cell adhesion molecules. In vitro some of the cell-adhesive functions of the β-subunits may play important physiological roles independently of the α-subunits. Other endogenous regulatory proteins named “ channel partners” or “ channel interacting proteins” (ChiPs) like caveolin-3 and calmodulin/calmodulin kinase II (CaMKII) can also interact and modulate the expression and/or function of VGSC. In addition to their physiological roles in cell excitability and cell adhesion, VGSC are the site of action of toxins (like tetrodotoxin and saxitoxin), and pharmacologic agents (like antiarrhythmic drugs, local anesthetics, antiepileptic drugs, and newly developed analgesics). Mutations in genes that encode α- and/or β-subunits as well as the ChiPs can affect the structure and biophysical properties of VGSC, leading to the development of diseases termed sodium “ channelopathies”.  This review will outline the structure, function, and biophysical properties of VGSC as well as their pharmacology and associated channelopathies and highlight some of the recent advances in this field.

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          Most cited references186

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          De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.

          Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development stagnates around the second year of life. Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epilepsy associated with febrile and afebrile seizures. Because both GEFS+ and SMEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient: four had frameshift mutations, one had a nonsense mutation, one had a splice-donor mutation, and one had a missense mutation. All mutations are de novo mutations and were not observed in 184 control chromosomes.
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            SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.

            Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.
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              Ion channel voltage sensors: structure, function, and pathophysiology.

              Voltage-gated ion channels generate electrical signals in species from bacteria to man. Their voltage-sensing modules are responsible for initiation of action potentials and graded membrane potential changes in response to synaptic input and other physiological stimuli. Extensive structure-function studies, structure determination, and molecular modeling are now converging on a sliding-helix mechanism for electromechanical coupling in which outward movement of gating charges in the S4 transmembrane segments catalyzed by sequential formation of ion pairs pulls the S4-S5 linker, bends the S6 segment, and opens the pore. Impairment of voltage-sensor function by mutations in Na+ channels contributes to several ion channelopathies, and gating pore current conducted by mutant voltage sensors in Na(V)1.4 channels is the primary pathophysiological mechanism in hypokalemic periodic paralysis. The emerging structural model for voltage sensor function opens the way to development of a new generation of ion-channel drugs that act on voltage sensors rather than blocking the pore. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Research Foundation
                1663-9812
                11 July 2012
                2012
                : 3
                : 124
                Affiliations
                [1] 1Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Nashville, TN, USA
                [2] 2Division of Cardiology, Department of Medicine and Cellular and Molecular Medicine, University of Ottawa Ottawa, ON, Canada
                Author notes

                Edited by: Jean-François Desaphy, University of Bari Aldo Moro, Italy

                Reviewed by: Massimo Mantegazza, University of Nice Sophia Antipolis, France; Peter Enyedi, Semmelweis University, Hungary

                *Correspondence: Dawood Darbar, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Room 1285A MRB IV, Nashville,TN 37323-6602, USA. e-mail: dawood.darbar@ 123456vanderbilt.edu

                This article was submitted to Frontiers in Pharmacology of Ion Channels and Channelopathies, a specialty of Frontiers in Pharmacology.

                Article
                10.3389/fphar.2012.00124
                3394224
                22798951
                ca102613-f840-4234-ab4a-d9432f236883
                Copyright © 2012 Savio-Galimberti, Gollob and Darbar.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 15 November 2011
                : 11 June 2012
                Page count
                Figures: 1, Tables: 3, Equations: 0, References: 205, Pages: 19, Words: 18636
                Categories
                Pharmacology
                Review Article

                Pharmacology & Pharmaceutical medicine
                sodium channels,electrophysiology,pharmacology,biophysics,voltage-gated sodium channels,channelopathies

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