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

• Published in: Philosophical transactions of the Royal Society of London. Series B. Biological sciences 2023-06, Vol.378 (1879), p.20220162-20220162
• Main Authors: Salvage, Samantha C, Dulhunty, Angela F, Jeevaratnam, Kamalan, Jackson, Antony P, Huang, Christopher L-H
• Format: Article
• Language: English
• Subjects: Action Potentials; Animals; Calcium - metabolism; Dantrolene - pharmacology; Feedback; Homeostasis and Excitation Contraction Coupling; Mice; Muscle, Skeletal; Part III: Ca; Review; Ryanodine Receptor Calcium Release Channel - chemistry; Ryanodine Receptor Calcium Release Channel - genetics
• ISSN: 0962-8436; 1471-2970
• DOI: 10.1098/rstb.2022.0162

Skeletal and cardiac muscle excitation-contraction coupling commences with Na 1.4/Na 1.5-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 Na 1.4/Na 1.5 function in native muscle. Finite-element modelling predicted potentially regulatory T-SR junctional [Ca ] domains. Na 1.4/Na 1.5, 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'.