Ca2+-dependent modulation of voltage-gated myocyte sodium channels.

Publisher: Portland Press On The Behalf Of The Biochemical Society Country of Publication: England NLM ID: 7506897 Publication Model: Print Cited Medium: Internet ISSN: 1470-8752 (Electronic) Linking ISSN: 03005127 NLM ISO Abbreviation: Biochem Soc Trans Subsets: MEDLINE

Original Publication: London : Portland Press On The Behalf Of The Biochemical Society

Calcium Signaling* ; Ion Channel Gating*; Calcium/*metabolism ; Myocytes, Cardiac/*metabolism ; NAV1.4 Voltage-Gated Sodium Channel/*metabolism ; NAV1.5 Voltage-Gated Sodium Channel/*metabolism ; Sodium/*metabolism; Action Potentials ; Animals ; Binding Sites ; Disease Models, Animal ; Flecainide/therapeutic use ; Humans ; Mice ; Ryanodine Receptor Calcium Release Channel/genetics ; Ryanodine Receptor Calcium Release Channel/metabolism ; Tachycardia, Ventricular/drug therapy ; Tachycardia, Ventricular/genetics ; Tachycardia, Ventricular/metabolism ; Treatment Outcome ; Voltage-Gated Sodium Channel Blockers/therapeutic use ; Polymorphic Catecholaminergic Ventricular Tachycardia

Voltage-dependent Na+ channel activation underlies action potential generation fundamental to cellular excitability. In skeletal and cardiac muscle this triggers contraction via ryanodine-receptor (RyR)-mediated sarcoplasmic reticular (SR) Ca2+ release. We here review potential feedback actions of intracellular [Ca2+] ([Ca2+]i) on Na+ channel activity, surveying their structural, genetic and cellular and functional implications, translating these to their possible clinical importance. In addition to phosphorylation sites, both Nav1.4 and Nav1.5 possess potentially regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III-IV linker and C-terminal domains (CTD), where mutations are associated with a range of skeletal and cardiac muscle diseases. We summarize in vitro cell-attached patch clamp studies reporting correspondingly diverse, direct and indirect, Ca2+ effects upon maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) characterizing channel gating, in cellular expression systems and isolated myocytes. Interventions increasing cytoplasmic [Ca2+]i down-regulated Imax leaving V1/2 constant in native loose patch clamped, wild-type murine skeletal and cardiac myocytes. They correspondingly reduced action potential upstroke rates and conduction velocities, causing pro-arrhythmic effects in intact perfused hearts. Genetically modified murine RyR2-P2328S hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT), recapitulated clinical ventricular and atrial pro-arrhythmic phenotypes following catecholaminergic challenge. These accompanied reductions in action potential conduction velocities. The latter were reversed by flecainide at RyR-blocking concentrations specifically in RyR2-P2328S as opposed to wild-type hearts, suggesting a basis for its recent therapeutic application in CPVT. We finally explore the relevance of these mechanisms in further genetic paradigms for commoner metabolic and structural cardiac disease.
(© 2021 The Author(s).)

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PG/19/59/34582 United Kingdom BHF_ British Heart Foundation; 105727/Z/14/Z United Kingdom WT_ Wellcome Trust; MR/M001288/1 United Kingdom AMS_ Academy of Medical Sciences; PG/14/79/31102 United Kingdom BHF_ British Heart Foundation; MR/M001288/1 United Kingdom MRC_ Medical Research Council

Keywords: C-terminal domain; ca2+; cardiac arrhythmia; cardiomyocytes; skeletal myocytes; sodium channels

0 (NAV1.4 Voltage-Gated Sodium Channel)
0 (NAV1.5 Voltage-Gated Sodium Channel)
0 (Ryanodine Receptor Calcium Release Channel)
0 (Voltage-Gated Sodium Channel Blockers)
0 (ryanodine receptor 2. mouse)
9NEZ333N27 (Sodium)
K94FTS1806 (Flecainide)
SY7Q814VUP (Calcium)

Date Created: 20211013 Date Completed: 20220221 Latest Revision: 20250103

20250114

PMC8589445

10.1042/BST20200604

34643236