Journal
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Volume 469, Issue 5-6, Pages 629-641Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00424-017-1959-1
Keywords
Sodium channel activation; Sodium channel inactivation; Late sodium current; Paramyotonia congenita; Cardiac arrhythmic syndromes
Categories
Funding
- Physiological Society, United Kingdom at University of Surrey
- Fundamental Research Grant Scheme [FRGS/2/2014/SKK01/PERDANA/02/1]
- Ministry of Education, Malaysia
- Faculty of Health and Medical Science, University of Surrey
- British Heart Foundation [PG/14/80/31106, PG/16/67/32340, PG/14/79/31102]
- Medical Research Council [G10002647, MR/M001288/1]
- Wellcome Trust [105727/Z/14/Z]
- McVeigh Benefaction
- SADS UK
- MRC [MR/M001288/1, G1002647] Funding Source: UKRI
- British Heart Foundation [PG/14/79/31102, PG/12/21/29473, PG/11/59/29006, PG/14/80/31106] Funding Source: researchfish
- Medical Research Council [973929, MR/M001288/1, G1002647] Funding Source: researchfish
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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 (I-Na) 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-L can 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-L are 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.
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