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

Skeletal and cardiac muscle excitation-contraction coupling commences with Na1.4/Na1.5-mediated, surface and transverse (T-) tubular, action potential generation. This initiates , allosteric or Ca-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 actions of the resulting SR Ca release on Na1.4/Na1.5 function in native muscle. Finite-element modelling predicted potentially regulatory T-SR junctional [Ca] domains. Na1.4/Na1.5, III-IV linker and C-terminal domain structures included Ca 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 () following SR Ca 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-ATPase inhibitor cyclopiazonic acid increased . Experimental, catecholaminergic polymorphic ventricular tachycardic and metabolically deficient cardiomyocytes also showed reduced accompanying [Ca] abnormalities rescued by dantrolene- and flecainide-mediated RyR block. Finally, hydroxychloroquine challenge implicated action potential (AP) prolongation in slowing AP conduction through modifying Ca transients. The corresponding tissue/organ preparations each showed pro-arrhythmic, slowed AP upstrokes and conduction velocities. We finally extend discussion of possible Ca-mediated effects to further, Ca, K and Cl, channel types. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.