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 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’.