title: Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes.
abstract: Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na+current components play critical parts. Early peak, Na+currents (INa) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na+currents (INa-L) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of INa-Lcan be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na+conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na+channel abnormalities increasing INa-Lare implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate INa-L. These include (1) overlaps between steady-state activation and inactivation increasing window current, (2) kinetic deficiencies in Na+channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) non-equilibrium gating processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased INa-L.
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, VSM Building, Guildford, GU2 7AL, UK.|Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
authors.forename: Karan R
authors.initials: KR
authors.lastname: Chadda
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, VSM Building, Guildford, GU2 7AL, UK.|School of Medicine, Perdana University-Royal College of Surgeons Ireland, 43400, Serdang, Selangor Darul Ehsan, Malaysia.
authors.forename: Kamalan
authors.initials: K
authors.lastname: Jeevaratnam
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK. clh11@cam.ac.uk.|Department of Biochemistry, University of Cambridge, Hopkins Building, Cambridge, CB2 1QW, UK. clh11@cam.ac.uk.
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D061566:Voltage-Gated Sodium Channels
keywords: Cardiac arrhythmic syndromes; Late sodium current; Paramyotonia congenita; Sodium channel activation; Sodium channel inactivation