Ryanodine receptors

Abstract

Excitation-contraction coupling involves the faithful conversion of electrical stimuli to mechanical shortening in striated muscle cells, enabled by the ubiquitous second messenger, calcium. Crucial to this process are ryanodine receptors (RyRs), the sentinels of massive intracellular calcium stores contained within the sarcoplasmic reticulum. In response to sarcolemmal depolarization, RyRs release calcium into the cytosol, facilitating mobilization of the myofilaments and enabling cell contraction. In order for the cells to relax, calcium must be rapidly resequestered or extruded from the cytosol. The sustainability of this cycle is crucially dependent upon precise regulation of RyRs by numerous cytosolic metabolites and by proteins within the lumen of the sarcoplasmic reticulum and those directly associated with the receptors in a macromolecular complex. In addition to providing the majority of the calcium necessary for contraction of cardiac and skeletal muscle, RyRs act as molecular switchboards that integrate a multitude of cytosolic signals such as dynamic and steady calcium fluctuations, β-adrenergic stimulation (phosphorylation), nitrosylation and metabolic states, and transduce these signals to the channel pore to release appropriate amounts of calcium. Indeed, dysregulation of calcium release via RyRs is associated with life-threatening diseases in both skeletal and cardiac muscle. In this paper, we briefly review some of the most outstanding structural and functional attributes of RyRs and their mechanism of regulation. Further, we address pathogenic RyR dysfunction implicated in cardiovascular disease and skeletal myopathies.

Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

“…4) will be absent until SR load increases again. In this scheme, sympathetic stimulation and activation of its downstream effector PKA favors RyR2-A4860G +/− arrhythmogenesis: in addition to phosphorylating RyR2 and promoting Ca 2+ release, PKA increases I CaL and accelerates SR Ca 2+ uptake (1,3,4), all of which would encourage activation of RyR2-A4860G channels. Nonetheless, because the mutation intrinsically hinders the activity of the RyR2 channel, the scheme predicts that EADs could be detected even in the absence of adrenergic stimulation, albeit at a lower rate.…”

“…3 H]ryanodine binding may be used as an index of channel activity (3,18), this indicates that a distinct number of RyR2 channels in RyR2-A4860G +/− hearts remain resilient to Ca 2+ activation, and their variable reduction of binding capacity in turn suggests that there is variable penetrance of the dysfunctional phenotype. The randomness in the assemblage of tetrameric channels containing a critical number of mutant monomers (Fig.…”

“…In their intracellular milieu, RyR2 channels are regulated by a variety of cytosolic and luminal factors so that their output signal (i.e., Ca 2+ ) finely grades cardiac contractions (3). However, RyR2 channels operate within a limited margin of safety because conditions that demand higher RyR2 activity (such as sympathetic stimulation) also increase the vulnerability of the heart to life-threatening arrhythmias (4), and this risk is higher in hearts harboring mutant RyR2 channels.…”

Structural and Molecular Bases of Sarcoplasmic Reticulum Ion Channel Function

“…To gain the functional flexibility necessary to respond to different triggering signals, at least three isoforms of RyR are expressed in mammals. 17,29,31 RyR1 is expressed predominantly in fast-and slow-twitch skeletal muscle and in cerebellar Purkinje cells. RyR2 is found in cardiac muscle (presumably the only isoform expressed there), but is also robustly expressed in the brain and in visceral and arterial smooth muscle.…”

Ligand-dependent Conformational Changes in the Clamp Region of the Cardiac Ryanodine Receptor

“…RyR can also be modulated by a number of pharmacological ligands (5,6). Altered RyR regulation by physiological ligands or abnormal RyR response to pharmacological ligands has been linked to muscle disorders such as heart failure, cardiac arrhythmias, and malignant hyperthermia (5,(7)(8)(9)(10)(11). Despite its important physiological and pathophysiological significance, the molecular mechanism of ligand modulation of RyR is largely undefined.…”