Pharmacology of ryanodine receptors and Ca²⁺‐induced Ca²⁺ release

Abstract

Ryanodine receptors (RyR) are cation-selective, ligand-modulated, ion channels that provide a pathway for the regulated release of Ca 2+ from intracellular reticular storage organelles to initiate a wide variety of cellular processes. In addition to regulation by endogenous ligands, the function of RyR can be altered by many pharmacological agents. Some of these have been used to establish the contribution of RyR-mediated Ca 2+ release to diverse signaling processes. Altered RyR function also plays a role in the development of diseases of both skeletal and cardiac muscles, hence both new and established compounds have potential as RyR-focussed therapeutic agents. efflux from the sarco/endoplasmic reticulum (SR/ER), and are responsible for triggering numerous Ca 2+ -activated physiological processes, the most widely studied of which is excitation-contraction coupling (ECC). This process occurs in the myocyte and describes the translation of the electrical impulse into physical contraction of the cell, and tissuespecific expression of RyR1 or RyR2 isoforms in skeletal or cardiac muscles, respectively, is essential for this. 1 The mechanism of activation for each isoform is different, the former being activated by the virtue of direct physical coupling with the L-type Ca 2+ channel, and the latter by Ca 2+ -induced Ca 2+ release (CICR). 1 Both are immense tetrameric channels (2.2MDa), composed of a relatively small pore region and a large cytoplasmic domain that serves to interact with a comprehensive set of accessory proteins thought to modulate channel function (reviewed elsewhere 2,3 ). Dysfunction of these RyRs, most commonly manifest as enhanced Ca 2+ release at rest (skeletal muscle) or during diastole (cardiac muscle), appears to be the fundamental mechanism underlying several genetic or acquired * Correspondence to: williamsaj9@cardiff.ac.uk Wales Heart Research Institute, Department of Medicine, Cardiff University, Cardiff, UK syndromes. Malignant hyperthermia (MH) and central core disease (CCD) are disorders of skeletal muscle, which cause muscle rigidity, respiratory and metabolic acidosis, and a dramatic rise in body temperature in response to halogenated anesthetics, and hypotonia/motor deficiencies, respectively, and are caused by mutations in RyR1. 4 In cardiac muscle, RyR2 mutations lead to catecholaminergic polymorphic ventricular tachycardia (CPVT1) and other cardiac arrhythmias. [5][6][7] Defective regulation of this channel has also been implicated in the development of arrhythmias in heart failure (HF). 8Investigation of the mechanisms behind channel dysfunction has been a steadily growing area of research over the last decade, and many of these studies have been in native or whole cell systems. As a result pharmacological tools have been required to evaluate or modulate RyR function in these disease models.Many articles have reviewed the basic pharmacology of the RyR, 9-12 and while these have been useful, listing the myriad compounds which affect channel function (ranging from its namesake r...

Role of capillary pericytes in the integration of spontaneous Ca2+ transients in the suburothelial microvasculature in situ of the mouse bladder

“…). In NG2(+) pericytes of PCAs, capillaries or PCVs in the same microvascular unit, spontaneous Ca 2+ transients were prevented or inhibited by both caffeine and tetracaine, a known blocker of CICR (Thomas & Williams, ), suggesting that CICR via RYRs is also involved in the spontaneous SR/ER Ca 2+ transients in NG2(+) pericytes distributed in these microvascular segments. Therefore, there may be heterogeneity in the role of RYRs in different microvascular segments.…”

“…In the suburothelial venules, spontaneous Ca 2+ transients in venular pericytes are abolished by blockers of IP 3 -induced Ca 2+ release but not ryanodine, suggesting that IP 3 receptors rather than ryanodine receptors (RYRs) play a predominant role in the spontaneous SR/ER Ca 2+ transients (Hashitani et al 2012). In NG2(+) pericytes of PCAs, capillaries or PCVs in the same microvascular unit, spontaneous Ca 2+ transients were prevented or inhibited by both caffeine and tetracaine, a known blocker of CICR (Thomas & Williams, 2012), suggesting that CICR via RYRs is also involved in the spontaneous SR/ER Ca 2+ transients in NG2(+) pericytes distributed in these microvascular segments. Therefore, there may be heterogeneity in the role of RYRs in different microvascular segments.…”

Investigations of the Contribution of a Putative Glycine Hinge to Ryanodine Receptor Channel Gating

“…Mutations within RyR2 are established as the underlying cause of the inherited disease catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) (2, 3); however, the mechanisms that lead to altered function are yet to be fully established. To gain an insight into how function is altered in mutant channels, we need greater knowledge of the structures involved in the ion permeation pathway and the mechanisms whereby transitions between open and nonconducting conformations occur.…”

Calcium Signaling Initiated by Agonists in Mesenchymal Stromal Cells from the Human Adipose Tissue

“…Initially, an agonist produced a Ca 2+ signal most likely being small, local, and gradually dependent on stimulus intensity. When exceeding the threshold, this local and poorly resolved Ca 2+ signal pushed massive Ca 2+ -induced Ca 2+ release (CICR) [37][38][39][40] to accomplish transduction with a large and global Ca 2+ signal. By involving the trigger-like mechanism CICR, a cell generates Ca 2+ responses of virtually universal shape and magnitude at different agonist concentrations above the threshold (Figure 2).…”