Approaching ryanodine receptor therapeutics from the calcin angle

The Rockefeller University Press $30.00 J. Gen. Physiol. 2016 Vol. 147 No. 5 369–373 www.jgp.org/cgi/doi/10.1085/jgp.201611599 369 Release of Ca from intracellular stores is a ubiquitous mechanism that contributes to numerous physiological processes, including secretion, transcription, apoptosis, and contraction. In many cases, the rise in intracellular Ca is mediated by Ca release channels called ryanodine receptors (RyRs) and involves a positive feedback mechanism known as Ca-induced Ca release (CICR). Just as normal RyR function is essential for life, abnormal RyR function can cause disease; notable examples include malignant hyperthermia (MH), central core disease, catecholaminergic polymorphic ventricular tachycardia, heart failure, and Alzheimer’s disease (Betzenhauser and Marks, 2010; Chakroborty and Stutzmann, 2014; Ríos et al., 2015). Thus, development of new therapeutic RyR-targeting drugs carries substantial clinical potential. In this issue, Xiao et al. comprehensively characterize a relatively new family of RyR ligands, the calcins. Several compounds have been examined as possible precursors of future RyR-targeting agents, the most famous being ryanodine, caffeine, and dantrolene. The ryanodine and caffeine actions are dramatic; consequently, these agents (to our knowledge) have not been extensively explored as potential precursors of future RyR therapies. Dantrolene and its derivatives are antagonists of RyR-mediated Ca release (Ikemoto et al., 2001), and dantrolene itself is an FDA-approved drug for the treatment of MH and spasms in skeletal muscle. Interestingly, dantrolene also appears to have neuroprotective (Liang and Wei, 2015) and antiarrhythmic actions (Penttinen et al., 2015). At issue, however, is the uncertainty surrounding the mechanism by which dantrolene limits RyR-mediated Ca release, which adds difficulty to assessing its potential as a precursor of future RyR-targeted agents. Another interesting class of RyR ligands is the benzothiazepine derivatives (e.g., JTV519 and S107). These agents purportedly stabilize the RyR–FK506 binding protein complex, but the underlying molecular mechanism remains controversial. This mechanistic uncertainty adds difficulty to predicting the potential of these agents as future therapeutic tools. On a positive note, the benzothiazepine derivatives do limit diastolic SR Ca leak and thus could help normalize the abnormally high Ca leak associated with heart failure (Betzenhauser and Marks, 2010). More recently, the β-blocker carvedilol and its derivatives have been forwarded as possible precursors of future RyR-targeting agents (Zhou et al., 2011; Zhang et al., 2015). Individual RyR openings become shorter when these compounds bind to the RyR, which limits diastolic SR Ca leak as well as the inter-RyR CICR that underlies dangerous propagating diastolic Ca waves. The danger arises because Ca waves can drive electrogenic Na–Ca exchange at the surface membrane that is sufficient to trigger delayed afterdepolarizations (DADs)—potentially life-threatening arrhythmogenic events. This antiwave action of carvedilol is unique among β-blockers but is unfortunately dose limited by its β-blocking capacity (Zhou et al., 2011). Therefore, carvedilol derivatives that shorten RyR openings without causing β-block have been generated (Zhou et al., 2011), and these have significant potential as precursors for the development of future RyR-targeting agents. Interestingly, The FDA-approved carvedilol (trade name: Coreg) is a racemic mixture that includes the non–β-blocking R-enantiomer, which shortens RyR openings. In addition, RyR up-regulation has been proposed to contribute to pathology in Alzheimer’s disease mouse models (Chakroborty and Stutzmann, 2014), and carvedilol appears to slow cognitive deterioration associated with Alzheimer’s disease (Wang et al., 2011), implying that non–β-blocking carvedilol derivatives may have additional clinical applications beyond the heart. The RyR-targeting drugs described above all work to restrain RyR function. In contrast, the recent study by Xiao et al. (2016) characterizes and compares eight calcins that enhance RyR activity, which makes calcins an intriguing prospect for future RyR drug development.