Ryanodine receptor channelopathies

Abstract

Ryanodine receptors (RyR) are intracellular Ca2+-permeable channels that provide the sarcoplasmic reticulum Ca2+ release required for skeletal and cardiac muscle contractions. RyR1 underlies skeletal muscle contraction, and RyR2 fulfills this role in cardiac muscle. Over the past 20 years, numerous mutations in both RyR isoforms have been identified and linked to skeletal and cardiac diseases. Malignant hyperthermia, central core disease, and catecholaminergic polymorphic ventricular tachycardia have been genetically linked to mutations in either RyR1 or RyR2. Thus, RyR channelopathies are both of interest because they cause significant human diseases and provide model systems that can be studied to elucidate important structure-function relationships of these ion channels.

Fig. 1

Disease-related mutations in human RyR1 and RyR2 are clustered in three mutational “hot spots.” a The tetrameric structure of RyR Ca²⁺ release channels with the membrane topology superimposed on one of the subunits. b The distribution of over 200 malignant hyperthermia and central core disease-causing mutations in human RyR1 and over 70 catecholaminergic polymorphic ventricular tachycardia-associated mutations in human RyR2

Fig. 2

Two different effects of central core disease-related mutations on skeletal muscle excitation–contraction coupling. a A cartoon depicting the effects of a leaky RyR1 mutation. This class of mutations exhibits an increased sensitivity to activation by membrane depolarization, Ca²⁺, caffeine, and halothane. b A cartoon depicting the effects of an uncoupled mutation. Mutations of this class lead to nonfunctional channels and increased sarcoplasmic reticulum Ca²⁺ store content

Fig. 3

Four different proposed mechanisms to explain how RyR2 mutations lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). a CPVT mutations are more sensitive to PKA hyperphosphorylation, which leads to depletion of the channel stabilizing protein, calstabin2 (FKBP12.6), and sarcoplasmic reticulum (SR) Ca²⁺ leak. b CPVT mutations lead to an increase in sensitivity to store-overload-induced Ca²⁺ release that is exacerbated by the increased SR store content triggered by stressful situations. c CPVT mutations lead to increased RyR2 sensitivity to activating agents such as caffeine, 4-CmC, or cAMP-mobilizing agents. d CPVT mutations lead to an unzippering of intramolecular interactions, which leads to increased diastolic SR Ca²⁺ leak

Fig. 4

Fixing sarcoplasmic reticulum (SR) Ca²⁺ leak by targeting RyR2–calstabin2 interactions. The traces in (a), (b), and (c) are representative telemetric electrocardiogram (ECG) recordings from wild type, R2474S heterozygous (R2474S^+/−) mice, and R2474S^+/− mice that were treated with S107. Mice were subjected to a stress protocol consisting of a treadmill exercise followed by epinephrine injections. Wild type mice did not exhibit irregular ECGs under these conditions, while a majority of R2474S^+/− mice exhibited severe ventricular tachycardias and sudden cardiac death (single asterisk, bidirectional VT; double asterisk, polymorphic VT). Treatment with S107 largely prevented these effects as shown by the regular ECG. Below the traces are cartoons depicting the condition of the RyR–calstabin2 complex under each experimental condition. Data were from Lehnart et al. [65] and reprinted with permission from the American Society of Clinical Investigation