Roles and regulation of the cardiac sodium channel Na v 1.5: recent insights from experimental studies.
During the past decade, Na(v)1.5, the main voltage-gated Na(+) channel in the heart, has been shown to be involved in many cardiac diseases. Genetic variants in the gene SCN5A, encoding Na(v)1.5, have been linked to various cardiac phenotypes, such as the congenital and acquired long QT syndromes, Brugada syndrome, conduction slowing, sick sinus syndrome, atrial fibrillation, and even cases of dilated cardiomyopathy. This unexpected phenotypic diversity may reflect that Na(v)1.5 is not only restricted to the initiation of the action potential and rapid cardiac conduction, but may also be involved in other, not-yet elucidated, functions. Despite the fact that our understanding of the regulation of expression, localization, and function of Na(v)1.5 is deepening, we are still far from a comprehensive view. Much of our current knowledge has been obtained by carrying out experiments using "cellular expression systems", e.g. host cells expressing exogenous Na(v)1.5. Although very informative, these techniques are limited, in that Na(v)1.5 is not expressed in the physiological cellular environment of a cardiac cell. Recently, however, there have been several studies published which used approaches closer to "normal" or pathological physiology. In an attempt to summarize recently published data, this article will review the phenotypes of genetically-modified mouse strains where Na(v)1.5 expression and activity are directly or indirectly modified, as well as the regulation of Na(v)1.5 function using native cardiac myocytes. Despite obvious limitations, the reviewed studies provide an overview of the complex multi-factorial and multi-protein regulation of Na(v)1.5.
Abriel
Hugues
H
University of Lausanne, Department of Pharmacology and Toxicology and Service of Cardiology, Bugnon, 27, 1005 Lausanne, Switzerland. hugues.abriel@unil.ch
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D006329:Heart Conduction System / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D032383:Myocytes, Cardiac / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels