Dynamic alterations in myoplasmic Ca2+ in malignant hyperthermia and central core disease.
Ca2+ ions play a pivotal role in a wide array of cellular processes ranging from fertilization to cell death. In skeletal muscle, a mechanical interaction between plasma membrane dihydropyridine receptors (DHPRs, L-type Ca2+ channels) and Ca2+ release channels (ryanodine receptors, RyR1s) of the sarcoplasmic reticulum orchestrates a complex, bi-directional Ca2+ signaling process that converts electrical impulses in the sarcolemma into myoplasmic Ca2+ transients during excitation-contraction coupling. Mutations in the genes that encode the two proteins that coordinate this electrochemical conversion process (the DHPR and RyR1) result in a variety of skeletal muscle disorders including malignant hyperthermia (MH), central core disease (CCD), multiminicore disease, nemaline rod myopathy, and hypokalemic periodic paralysis. Although RyR1 and DHPR disease mutations are thought to alter excitability and Ca2+ homeostasis in skeletal muscle, only recently has research begun to probe the molecular mechanisms by which these genetic defects lead to distinct clinical and histopathological manifestations. This review focuses on recent advances in determining the impact of MH and CCD mutations in RyR1 on muscle Ca2+ signaling and how these effects contribute to disease-specific aspects of these disorders.
Lyfenko
Alla D
AD
Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Goonasekera
Sanjeewa A
SA
Dirksen
Robert T
RT
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006801:Humans; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009200:Myocardial Contraction; D020512:Myopathy, Central Core / Q000235:genetics* / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium