The role of the calcium release channel of skeletal muscle sarcoplasmic reticulum in malignant hyperthermia.
In this short review, we have described studies that have identified Arg415 in the Ca2+ release channel as a residue that influences channel sensitivity to Ca2+ induced Ca2+ release, rate of Ca2+ release, and channel closing. We have also described studies that confirm Dr. Numa's predictions that residues 4246-4267, 4382-4417, and 4478-4512 contain Ca2+ binding sites. The site between residues 4483 and 4494 (the PE repeat sequence) may be a key binding site for Ca2+ activation of the channel. Other residues in the sequence 4478-4512 may also contribute to activation of the channel. Thus our studies have contributed to basic knowledge of regulation of Ca2+ release function. They have also provided practical benefits in defining a disease gene, in development of a diagnostic test for porcine MH that is of economic benefit, and in laying the foundation for human MH diagnostic tests that may prevent anesthesia-induced morbidity and mortality.
MacLennan
D H
DH
Banting and Best Department of Medical Research, University of Toronto, Charles H. Best Institute, Ontario, Canada.
Chen
S R
SR
D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D006801:Humans; D008305:Malignant Hyperthermia / Q000175:diagnosis / Q000235:genetics* / Q000662:veterinary; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D017354:Point Mutation; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D013552:Swine; D013553:Swine Diseases / Q000235:genetics
D015220:Calcium Channels; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D001120:Arginine; D002118:Calcium