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

Abstract

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.

Cardiomyocyte electrophysiology and its modulation: current views and future prospects

“…[ 51 ]) by further, downstream, excitation–contraction coupling (§5) and metabolic events (§7). All these effects were recapitulated in loss [ 52 , 53 ] or gain of function genetic murine models affecting Nav1.5 [ 54 , 55 ] and RyR2 function [ 56 , 57 ], and metabolic activation [ 23 , 58 , 59 ]. Furthermore, electrophysiological aberrations and arrhythmic tendency in the BrS and LQTS3 models were similarly accentuated or relieved by flecainide and ameliorated or accentuated by quinidine [ 53 , 60 ], findings with potential translational significance [ 61 , 62 ].…”

“…Salvage et al . [ 24 ] review this action, likely involving Ca 2+ /calmodulin (Ca 2+ -CaM) and apo-CaM interactions with binding sites on the III–IV linker and the C-terminal domain of Nav1.5 [ 57 ]. Such mechanisms appear to operate through a wide range of physiological situations.…”

How does flecainide impact RyR2 channel function?

“…Elevated diastolic Ca 2+ may also downregulate Na V 1.5 and therefore I Na as demonstrated in the homozygous RyR2-P2328S +/+ mouse ( Ning et al, 2016 ). Here, Ca 2+ as a second messenger can target a number of signaling pathways which could lead to diminished I Na and thereby provide a further safety margin ( Luo et al, 2017 ; Ning et al, 2016 ; Casini et al, 2009 ; Salvage et al, 2021b ). Indirect effects of flecainide on NCX function are well recognized ( Bannister et al, 2015 ; Sikkel et al, 2013 ; Steele et al, 2013 ) and arise from the direct inhibition of I Na which in turn reduces cytosolic [Na + ], and therefore the driving force for reverse mode Ca 2+ influx.…”

Emergent Electrical Activity, Tissue Heterogeneity, and Robustness in a Calcium Feedback Regulatory Model of the Sinoatrial Node

“…Further, Ca i dynamics are tightly correlated with the transmembrane potential under normal conditions, such that Ca i is an appropriate sensor of cellular electrical activity. Finally, Ca i is an ubiquitous intracellular second messenger, implicated in a wide range of regulatory pathways, which can control protein expression or act directly on membrane channels to modulate their activity in neurons [22, 23], cardiomyocytes [24, 25, 26] and in particular in the SAN [27, 28].…”