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

Abstract

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 Ca 2+ -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 Ca 2+ release on Na v 1.4/Na v 1.5 function in native muscle. Finite-element modelling predicted potentially regulatory T-SR junctional [Ca 2+ ] TSR domains. Na v 1.4/Na v 1.5, III-IV linker and C-terminal domain structures included Ca 2+ 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 Ca 2+ 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 Ca 2+ -ATPase inhibitor cyclopiazonic acid increased I Na. Experimental, catecholaminergic polymorphic ventricular tachycardic RyR2-P2328S and metabolically deficient Pgc1β -/- cardiomyocytes also showed reduced I Na accompanying [Ca 2+ ] i abnormalities rescued by dantrolene- and flecainide-mediated RyR block. Finally, hydroxychloroquine challenge implicated action potential (AP) prolongation in slowing AP conduction through modifying Ca 2+ transients. The corresponding tissue/organ preparations each showed pro-arrhythmic, slowed AP upstrokes and conduction velocities. We finally extend discussion of possible Ca 2+ -mediated effects to further, Ca 2+, K + and Cl -, channel types. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.