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Regulation of Cardiac Voltage-Gated Sodium Channel by Kinases: Roles of Protein Kinases A and C

  • Ademuyiwa S. Aromolaran
  • Mohamed Chahine
  • Mohamed Boutjdir
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 246)

Abstract

In the heart, voltage-gated sodium (Nav) channel (Nav1.5) is defined by its pore-forming α-subunit and its auxiliary β-subunits, both of which are important for its critical contribution to the initiation and maintenance of the cardiac action potential (AP) that underlie normal heart rhythm. The physiological relevance of Nav1.5 is further marked by the fact that inherited or congenital mutations in Nav1.5 channel gene SCN5A lead to altered functional expression (including expression, trafficking, and current density), and are generally manifested in the form of distinct cardiac arrhythmic events, epilepsy, neuropathic pain, migraine, and neuromuscular disorders. However, despite significant advances in defining the pathophysiology of Nav1.5, the molecular mechanisms that underlie its regulation and contribution to cardiac disorders are poorly understood. It is rapidly becoming evident that the functional expression (localization, trafficking and gating) of Nav1.5 may be under modulation by post-translational modifications that are associated with phosphorylation. We review here the molecular basis of cardiac Na channel regulation by kinases (PKA and PKC) and the resulting functional consequences. Specifically, we discuss: (1) recent literature on the structural, molecular, and functional properties of cardiac Nav1.5 channels; (2) how these properties may be altered by phosphorylation in disease states underlain by congenital mutations in Nav1.5 channel and/or subunits such as long QT and Brugada syndromes. Our expectation is that understanding the roles of these distinct and complex phosphorylation processes on the functional expression of Nav1.5 is likely to provide crucial mechanistic insights into Na channel associated arrhythmogenic events and will facilitate the development of novel therapeutic strategies.

Keywords

Brugada syndrome Long QT syndrome 3 Protein kinase A Protein kinase C Voltage-gated sodium channel 

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Ademuyiwa S. Aromolaran
    • 1
    • 2
  • Mohamed Chahine
    • 3
    • 4
  • Mohamed Boutjdir
    • 1
    • 2
    • 5
  1. 1.Cardiovascular Research Program, VA New York Harbor Healthcare SystemBrooklynUSA
  2. 2.Departments of Medicine, Cell Biology and PharmacologyState University of New York Downstate Medical CenterBrooklynUSA
  3. 3.CERVO Brain Research CenterInstitut Universitaire en Santé Mentale de QuébecQuebec CityCanada
  4. 4.Department of MedicineUniversité LavalQuebec CityCanada
  5. 5.Department of MedicineNew York University School of MedicineNew YorkUSA

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