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

Abstract

In the heart, voltage-gated sodium (Na) channel (Na1.5) 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 Na1.5 is further marked by the fact that inherited or congenital mutations in Na1.5 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 Na1.5, 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 Na1.5 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 Na1.5 channels; (2) how these properties may be altered by phosphorylation in disease states underlain by congenital mutations in Na1.5 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 Na1.5 is likely to provide crucial mechanistic insights into Na channel associated arrhythmogenic events and will facilitate the development of novel therapeutic strategies.

Co-expression networks uncover regulation of splicing and transcription markers of disease

“…For the receptor treatment O, genes in the network are annotated to the Glutamatergic synapse pathway, and it is in accordance with previous reports [10,29]. Among the genes that exhibited a high degree treatment specificity, the function of Nav1.5 channel gene SCN5A in neuropathic pain and migraine has been reported [30,31]. Further exploration of the networks of additional pain sensitivity-related treatments will advancing the understanding of the molecular mechanism underlying these conditions.…”

Riluzole promotes neurological function recovery and inhibits damage extension in rats following spinal cord injury: a meta‐analysis and systematic review

“…; Aromolaran et al . ), may represent a mechanism of action by which riluzole reduces oxidative stress (Cai et al . ; Guo et al .…”

“…Finally, riluzole can protect against mitochondrial dysfunction and oxidative stress (Shimizu et al 2018). The regulation of PKC and AMP-activated protein kinase signals (Noh et al 2000;Daniel et al 2013;Mehnert et al 2018), induced by the overactivation of glutamate receptors or ion channels (Campana et al 2017;Aromolaran et al 2018), may represent a mechanism of action by which riluzole reduces oxidative stress (Cai et al 2017;Guo et al 2018).…”

Phosphorylation of cardiac voltage‐gated sodium channel: Potential players with multiple dimensions

“…PKA is a downstream effector of the β‐AR signalling pathway and plays an important role in cardiac excitation‐contraction coupling . In cardiomyocytes, β‐AR couples with stimulatory Gs protein and stimulation of the adrenergic system produces cAMP which activates PKA.…”