Feedback contributions to excitation-contraction coupling in native functioning striated muscle

Skeletal and cardiac muscle excitation-contraction coupling commences with Na(v)1.4/Na(v)1.5-mediated, surface and transverse (T-) tubular, action potential generation. This initiates feedforward, allosteric or Ca2+-mediated, T-sarcoplasmic reticular (SR) junctional, voltage sensor-Cav1.1/Cav1.2 and ryanodine receptor-RyR1/RyR2 interaction. We review recent structural, physiological and translational studies on possible feedback actions of the resulting SR Ca2+ release on Na(v)1.4/Na(v)1.5 function in native muscle. Finite-element modelling predicted potentially regulatory T-SR junctional [Ca2+](TSR) domains. Na(v)1.4/Na(v)1.5, III-IV linker and C-terminal domain structures included Ca2+ and/or calmodulin-binding sites whose mutations corresponded to specific clinical conditions. Loose-patch-clamped native murine skeletal muscle fibres and cardiomyocytes showed reduced Na+ currents (I-Na) following SR Ca2+ release induced by the Epac and direct RyR1/RyR2 activators, 8-(4-chlorophenylthio)adenosine-3 ',5 '-cyclic monophosphate and caffeine, abrogated by the RyR inhibitor dantrolene. Conversely, dantrolene and the Ca2+-ATPase inhibitor cyclopiazonic acid increased I-Na. Experimental, catecholaminergic polymorphic ventricular tachycardic RyR2-P2328S and metabolically deficient Pgc1 beta(-/-) cardiomyocytes also showed reduced I-Na accompanying [Ca2+](i) abnormalities rescued by dantrolene- and flecainide-mediated RyR block. Finally, hydroxychloroquine challenge implicated action potential (AP) prolongation in slowing AP conduction through modifying Ca2+ transients. The corresponding tissue/organ preparations each showed pro-arrhythmic, slowed AP upstrokes and conduction velocities. We finally extend discussion of possible Ca2+-mediated effects to further, Ca2+, K+ and Cl-, channel types.This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Automated summary

Skeletal and cardiac muscle excitation-contraction coupling involves the interaction between Na(v)1.4/Na(v)1.5 and Cav1.1/Cav1.2 channels, as well as RyR1/RyR2 receptors, mediated by SR Ca2+ release. Studies have shown the potential feedback actions of SR Ca2+ release on Na(v)1.4/Na(v)1.5 function. Experimental observations have revealed the effects of RyR inhibitors and activators on Na+ currents in muscle fibers and cardiomyocytes. The modulation of Ca2+ transients and AP conduction has implications for arrhythmogenicity.