Malignant hyperthermia: excitation-contraction coupling, Ca2+ release channel, and cell Ca2+ regulation defects

Abstract

Malignant hyperthermia (MH) is a disorder of skeletal muscle in which certain anesthetic agents trigger a sustained elevation in myoplasmic Ca2+ concentration that activates metabolic and contractile activity. This review focuses on the biochemical and physiological alterations in the skeletal muscle of MH-susceptible (MHS) pigs and humans that appear responsible for this inherited disorder. In porcine MH, these studies identified the skeletal muscle sarcoplasmic reticulum Ca2+ release channel gene (RYR1) as the site of the defect. A mutation in this protein results in altered excitation-contraction coupling and secondary changes in porcine muscle structure and function. Although RYR1 mutations have been reported in many MHS human families, there is also significant genetic heterogeneity, and much less is known as to the underlying mechanism responsible for altered human myoplasmic Ca2+ regulation. The effects of caffeine and anesthetic agents on MHS and normal muscle are also discussed to better understand the basis for the in vitro clinical test for this disorder and mechanisms responsible for the initiation and maintenance of MH episodes in susceptible individuals. Finally, we examine the possiblity of a defect in Ca2+ regulation in tissues other than skeletal muscle. Current understanding of the molecular basis of MH elegantly illustrates the successful integration of knowledge obtained from all fields of biological and clinical science.

Sarcoplasmic reticulum Ca2+ release channel ryanodine receptor (RyR2) plays a crucial role in aconitine-induced arrhythmias

“…Ca 2+ release from SR through the cardiac RyR 2 channel is a fundamental event in cardiac muscle contraction, which is triggered by calcium-induced calcium release (CICR) [11]. Alterations in the sensitivity of RyR 2 to Ca 2+ release activation have been implicated in diseases including malignant hyperthermia and heart failure [12][13][14]. Mutations in RyR 2 that are suspected to cause defective Ca 2+ channel function and aberrant intracellular Ca 2+ signals have recently been identified in catecholaminergic polymorphic ventricular tachycardia (CPVT) and arrhythmogenic right ventricular dysplasia (ARVD) patients [15].…”

Recent advances in the diagnosis of malignant hyperthermia susceptibility: How confident can we be of genetic testing?

“…Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive Introduction Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle calcium regulation. 1 On exposure to certain anaesthetic agents (halogenated inhalational anaesthetics and depolarising muscle relaxants) susceptible patients may experience a range of symptoms, including skeletal muscle rigidity (from masseter spasms to generalised rigidity), metabolic acidosis, tachycardia and fever, as a consequence of an abnormally high release of intracellular calcium in skeletal muscle. The condition is potentially life threatening and is one of the main causes of morbidity and mortality during general anaesthesia.…”

Multigenerational Brazilian family with malignant hyperthermia and a novel mutation in the RYR1 gene

“…Individuals who are susceptible to MH develop a hypermetabolic crisis after the administration of volatile general anesthetics and/or succinylcholine, with signs of tachycardia, arrhythmia, muscle rigidity, and hyperthermia. This life-threatening condition is caused by the increased release of Ca 2+ from the sarcoplasmic reticulum to the cytoplasm by the ryanodine receptor 1 (RyR1) (3).…”