MALIGNANT HYPERTHERMIA - EXCITATION-CONTRACTION COUPLING, CA2+ RELEASE CHANNEL, AND CELL CA2+ REGULATION DEFECTS

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 i n the skeletal muscle of MH-susceptible (MHS) pigs and humans that app ear responsible for this inherited disorder. In porcine MH, these stud ies identified the skeletal muscle sarcoplasmic reticulum Ca2+ release channel gene (RYR1) as the site of the defect. A mutation in this pro tein results in altered excitation-contraction coupling and secondary changes in porcine muscle structure and func tion. Although RYR1 mutat ions have been reported in many MHS human families, there is also sign ificant genetic heterogeneity, and much less is known as to the underl ying mechanism responsible for altered human myoplasmic Ca2+ regulatio n. The effects of caffeine and anesthetic agents on MHS and normal mus cle are also discussed to better understand the basis for the in vitro clinical test for this disorder and mechanisms responsible for the in itiation and maintenance of MH episodes in susceptible individuals. Fi nally, we examine the possibility of a defect in Ca2+ regulation in ti ssues other than skeletal muscle. Current understanding of the molecul ar basis of MH elegantly illustrates the successful integration of kno wledge obtained from all fields of biological and clinical science.