Action potential production, which is essential for neuronal excitability, is governed by voltage-dependent Na+ channel activation. This causes contraction in skeletal and cardiac muscle via sarcoplasmic reticular (SR) Ca2+ release mediated by the ryanodine receptor (RyR). The authors of this review examined the structural, cellular, genetic, and functional implications of potential intracellular [Ca2+] ([Ca2+]i) feedback actions on Na+ channel activity, as well as their potential clinical significance. They review in vitro cell-attached patch-clamp experiments in cellular expression systems and isolated myocytes, reporting a variety of direct and indirect Ca2+ effects on maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) that characterize channel gating.

Both Nav1.4 and Nav1.5 include potential regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III-IV linker and C-terminal domains (CTD), where mutations have been linked to a variety of skeletal and cardiac muscle disorders. In native loose patch clamped, wild-type mouse skeletal and cardiac myocytes, interventions that increased cytoplasmic [Ca2+]i decreased Imax while keeping V1/2 unchanged. Furthermore, they caused pro-arrhythmic effects in intact perfused hearts by lowering action potential upstroke rates and conduction velocities. The clinical ventricular and atrial pro-arrhythmic characteristics following the catecholaminergic challenge were replicated in genetically engineered mouse RyR2-P2328S hearts modeling catecholaminergic polymorphic ventricular tachycardia (CPVT). These were accompanied by slower conduction velocities of action potentials. Flecainide at RyR-blocking doses reversed the latter in RyR2-P2328S hearts but not in wild-type hearts, implying a rationale for its current therapeutic application in CPVT.

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Keywords

Disease condition,Arrhythmias,Ventricular Tachycardia

Source

https://pubmed.ncbi.nlm.nih.gov/34643236/

Tags

Disease Condition ,Arrhythmias,Ventricular Tachycardia