Affiliation:
1. Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam UMC (location AMC), University of Amsterdam, Amsterdam Cardiovascular Sciences, Meigberdreef 15, 1105AZ Amsterdam, The Netherlands
2. The Leon H. Charney Division of Cardiology, New York University School of Medicine, 435 E 30th St, NSB 707, New York, NY 10016, USA
Abstract
Abstract
The cardiac sodium channel NaV1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some NaV1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective NaV1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the NaV1.5 complex. In this alternative view, alterations in NaV1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of NaV1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through NaV1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of NaV1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of NaV1.5 is essential for the development of novel preventive and therapeutic strategies.
Funder
Innovational Research Incentives Scheme Vidi
Netherlands Organisation for Health Research and Development
Dutch Heart Foundation
Netherlands CardioVascular Research Initiative CVON
Dutch Federation of University Medical Centres
Royal Netherlands Academy of Sciences
Fondation Leducq Transatlantic Network of Excellence
Publisher
Oxford University Press (OUP)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
49 articles.
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