Potential for pharmacology of ryanodine receptor/calcium release channels

Calcium release channels, known also as ryanodine receptors (RyRs), play an important role in Ca2+ signaling in muscle and nonmuscle cells by releasing Ca2+ from intracellular stores. Mammalian tissues express three different RyR isoforms comprising four 560-kDa (RyR polypeptide) and four 12-kDa (FK506 binding protein) subunits. The large protein complexes conduct monovalent and divalent cations and are capable of multiple interactions with other molecules. The latter include small diffusible endogenous effector molecules including Ca2+, Mg2+, adenine nucleotides, sufhydryl modifying reagents (glutathione, NO, and NO adducts) and lipid intermediates, and proteins such as protein kinases and phosphatases, calmodulin, immunophilins (FK506 binding proteins), and in skeletal muscle the dihydropyridine receptor. Because of their role in regulating intracellular Ca2+ levels and their multiple ligand interactions, RyRs constitute an important, potentially rich pharmacological target for controlling cellular functions. Exogenous effectors found to affect RyR function include ryanoids, toxins, xanthines, anthraquinones, phenol derivatives, adenosine and purinergic agonists and antagonists, NO donors, oxidizing reagents, dantrolene, local anesthetics, and polycationic reagents.