Ryanodinopathies: RyR-Linked Muscle Diseases

doi:10.1016/S1063-5823(10)66007-3

Current Topics in Membranes

Volume 66, 2010, Pages 139-167

https://doi.org/10.1016/S1063-5823(10)66007-3 Get rights and content

Publisher Summary

This chapter examines the clinical characteristics, genetics, and pathophysiological mechanisms of the ryanodinopathies, an eclectic array of clinically distinct muscle disorders caused by inherited and acquired alterations in skeletal and cardiac muscle ryanodine receptor (RyR) function. Ryanodinopathies results from mutations and functional alterations in the skeletal—RyR1—and cardiac—RyR2—muscle RyRs. RyR1 mutations are linked to malignant hyperthermia (MH), a hypermetabolic pharmacogenetic disorder of skeletal muscle triggered by volatile anesthetics and several congenital myopathies, including central core disease (CCD), multi-minicore disease, core-rod myopathy, and centronuclear myopathy. The chapter discusses the potential mechanism by which RyR disease mutations alter channel sensitivity, leak, and release: (1) RyR hyperphosphorylation and FK506 binding protein (FKBP) dissociation, (2) disruption of critical RyR interdomain regulatory interactions, (3) enhanced store overload-induced Ca²⁺release, and (4) reduced RyR-mediated Ca²⁺ ﬂux because of altered channel gating or Ca²⁺permeation.

Section snippets

Overview

Ryanodine receptors (RyRs) are the primary intracellular Ca²⁺ release channels responsible for providing Ca²⁺ used to drive muscle contraction. Given this central role, it is not surprising that several debilitating and life-threatening muscle disorders, collectively termed “ryanodinopathies,” result from mutations and functional alterations in the skeletal (RyR1) and cardiac (RyR2) muscle RyRs. RyR1 mutations are linked to malignant hyperthermia (MH), a hypermetabolic pharmacogenetic disorder

Malignant Hyperthermia

MH is an autosomal dominant pharmacogenetic disorder characterized as a hypermetabolic state of skeletal muscle induced by potent volatile anesthetics (e.g., halothane, isoflurane, sevoflurane) and/or depolarizing muscle relaxants (e.g., succinylcholine). Triggering agents cause sustained Ca²⁺ release from the SR, which leads to contracture of skeletal muscle, glycogenolysis, and uncontrolled muscle metabolism that result in increased heat and lactate production. MH episodes are initially

Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT is among the most malignant of the many cardiac arrhythmias caused by malfunction of cardiac ion channels. CPVT was first recognized in the early 1970s, and described in detail in 1995 (Leenhardt et al., 1995). The incidence of CPVT is estimated to be ~ 1:10,000 (Yano et al., 2006) with about half of all patients exhibiting autosomal dominantly inherited mutations in the cardiac RYR2 gene (locus 1q42-43, Laitinen et al., 2001; Fig. 1). Approximately 2% of CPVT patients are associated with

Conclusions and Perspectives

This chapter reviews the presentation, genetics, pathophysiology, and treatment of the ryanodinopathies, an eclectic mix of clinically distinct muscle diseases that arise from genetically inherited and acquired alterations in skeletal and cardiac muscle RyR function. Given their central role in controlling dynamic and steady-state calcium homeostasis and striated muscle contraction, it is not surprising that alterations in RyR1 and RyR2 function result in several life-altering and -threatening

Acknowledgments

This work is supported by a research grant from the National Institutes of Health (AR044657 and AR053349 to R. T. D.) and the Academia Dei Lincei Fund (to L. W.).

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Cited by (7)

Characterization of ryanodine receptor type 1 single channel activity using "on-nucleus" patch clamp
2014, Cell Calcium
Citation Excerpt :
Further, since burgeoning numbers of RyR mutations are associated with multiple distinct disease states [56,57], this report provides a powerful experimental paradigm to characterize the properties of these mutant channels, as well as the molecular determinants of RyR channel modulation, within the context in a native cellular membrane compartment and with minimal disruption of the channel complex.
In this study, we provide the first description of the biophysical and pharmacological properties of ryanodine receptor type 1 (RyR1) expressed in a native membrane using the on-nucleus configuration of the patch clamp technique. A stable cell line expressing rabbit RyR1 was established (HEK-RyR1) using the FLP-in 293 cell system. In contrast to untransfected cells, RyR1 expression was readily demonstrated by immunoblotting and immunocytochemistry in HEK-RyR1 cells. In addition, the RyR1 agonists 4-CMC and caffeine activated Ca²⁺ release that was inhibited by high concentrations of ryanodine. On nucleus patch clamp was performed in nuclei prepared from HEK-RyR1 cells. Raising the [Ca²⁺] in the patch pipette resulted in the appearance of a large conductance cation channel with well resolved kinetics and the absence of prominent subconductance states. Current versus voltage relationships were ohmic and revealed a chord conductance of ∼750 pS or 450 pS in symmetrical 250 mM KCl or CsCl, respectively. The channel activity was markedly enhanced by caffeine and exposure to ryanodine resulted in the appearance of a subconductance state with a conductance ∼40% of the full channel opening with a P_o near unity. In total, these properties are entirely consistent with RyR1 channel activity. Exposure of RyR1 channels to cyclic ADP ribose (cADPr), nicotinic acid adenine dinucleotide phosphate (NAADP) or dantrolene did not alter the single channel activity stimulated by Ca²⁺, and thus, it is unlikely these molecules directly modulate RyR1 channel activity. In summary, we describe an experimental platform to monitor the single channel properties of RyR channels. We envision that this system will be influential in characterizing disease-associated RyR mutations and the molecular determinants of RyR channel modulation.
Interactions among ryanodine receptor isotypes contribute to muscle fiber type development and function
2020, DMM Disease Models and Mechanisms
Mutations affecting ryanodine receptor (RyR) calcium release channels commonly underlie congenital myopathies. Although these channels are known principally for their essential roles in muscle contractility, mutations in the human RYR1 gene result in a broad spectrum of phenotypes, including muscle weakness, altered proportions of fiber types, anomalous muscle fibers with cores or centrally placed nuclei, and dysmorphic craniofacial features. Currently, it is unknown which phenotypes directly reflect requirements for RyRs and which result secondarily to aberrant muscle function. To identify biological processes requiring RyR function, skeletal muscle development was analyzed in zebrafish embryos harboring protein-null mutations. RyR channels contribute to both muscle fiber development and function. Loss of some RyRs had modest effects, altering muscle fiber-type specification in the embryo without compromising viability. In addition, each RyR-encoding gene contributed to normal swimming behavior and muscle function. The RyR channels do not function in a simple additive manner. For example, although isoform RyR1a is sufficient for muscle contraction in the absence of RyR1b, RyR1a normally attenuates the activity of the co-expressed RyR1b channel in slow muscle. RyR3 also acts to modify the functions of other RyR channels. Furthermore, diminished RyR-dependent contractility affects both muscle fiber maturation and craniofacial development. These findings help to explain some of the heterogeneity of phenotypes that accompany RyR1 mutations in humans.
Summary: Skeletal muscle fiber development and function are dependent on additive as well as combinatorial interactions among ryanodine receptor calcium release channels.
Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review
2023, Journal of Clinical Medicine
Malignant hyperthermia: A systematic review
2019, Indian Journal of Public Health Research and Development
Role of defective Ca<sup>2+</sup> signaling in skeletal muscle weakness: Pharmacological implications
2018, Journal of Cell Communication and Signaling
Malignant hyperthermia: a review
2015, Orphanet Journal of Rare Diseases

View all citing articles on Scopus

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Chapter 7 - Ryanodinopathies: RyR-Linked Muscle Diseases

Publisher Summary

Section snippets

Overview

Malignant Hyperthermia

Catecholaminergic Polymorphic Ventricular Tachycardia

Conclusions and Perspectives

Acknowledgments

Pharmacology and Therapeutics

Human Pathology

Neuromuscular Disorders

Lancet

Lancet

Trends in Cardiovascular Medicine

Biophysical Journal

American Journal of Medicine

The Journal of Biological Chemistry

Cell

Biophysical Journal

Genomics

The Journal of Biological Chemistry

British Journal of Anaesthesia

Trends in Cardiovascular Medicine

The Journal of Biological Chemistry

NeuromuscularDisorders

Journal of the American College of Cardiology

American Journal of Human Genetics

Biophysical Journal

The American Journal of Medicine

Cell

Neuromuscular Disorders

American Journal of Human Genetics

Biochemical and Biophysical Research Communications

Trends in Molecular Medicine

Forensic Science International

Neuromuscular Disorders

Journal of the American College of Cardiology

The Journal of Biological Chemistry

Oxidative stress in SEPN1-related myopathy: From pathophysiology to treatment

Annals of Neurology

Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor

The Journal of General Physiology

Excitation–contraction uncoupling by a human central core disease mutation in the ryanodine receptor

Proceedings of the National Academy of Sciences of the United States of America

The pore region of the skeletal muscle ryanodine receptor is a primary locus for excitation-contraction uncoupling in central core disease

The Journal of General Physiology

Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning

The EMBO Journal

Characterization and temporal development of cores in a mouse model of malignant hyperthermia

Proceedings of the National Academy of Sciences of the United States of America

The relationship between exertional heat illness, exertional rhabdomyolysis, and malignant hyperthermia

Anesthesia and Analgesia

The role of CACNA1S in predisposition to malignant hyperthermia

BMC Medical Genetics

Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors

Journal of Clinical Investigation

Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiacryanodine receptor

Circulation Research

Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse

The FASEB Journal

Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3

The Journal of Neuroscience

Enhanced excitation-coupled calcium entry in myotubes expressing malignant hyperthermia mutation R163C is attenuated by dantrolene

Molecular Pharmacology

Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca2+ leak independent of luminal Ca2+ and trigger ventricular arrhythmias in mice

Circulation Research

Congenital long QT syndrome

Orphanet Journal of Rare Diseases

Anesthetic- and heat-induced sudden death in calsequestrin-1-knockout mice

The FASEB Journal

The association of malignant hyperthermia and unusual disease: When you're hot you're hot or maybe not

Anesthesia and Analgesia

Bi-directional coupling between dihydropyridine receptors and ryanodine receptors

Frontiers in Bioscience

Increased Ca2+ sensitivity of the ryanodine receptor mutant RyR2R4496C underlies catecholaminergic polymorphic ventricular tachycardia

Circulation Research

A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene

Annals of Neurology

Modest reductions of cardiac calsequestrin increase sarcoplasmic reticulum Ca²⁺ leak independent of luminal Ca²⁺ and trigger ventricular arrhythmias in mice

Increased Ca²⁺ sensitivity of the ryanodine receptor mutant RyR2R4496C underlies catecholaminergic polymorphic ventricular tachycardia