title: Novel regulators of RyR Ca2+ release channels: insight into molecular changes in genetically-linked myopathies.
abstract: There are many mutations in the ryanodine receptor (RyR) Ca2+ release channel that are implicated in skeletal muscle disorders and cardiac arrhythmias. More than 80 mutations in the skeletal RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in the cardiac RyR2 lead to ventricular arrhythmias and sudden cardiac death in patients with structurally normal hearts. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling in the muscle fibres. In a different myopathy, myotonic dystrophy (DM), a juvenile isoform of the skeletal RyR is preferentially expressed in adults. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). The juvenile isoform (ASI(-)) is less active than the adult isoform (ASI(+)) and its over-expression in adults with DM may contribute to functional changes. Finally, mutations in an important regulator of the RyR, the Ca2+ binding protein calsequestrin (CSQ), have been linked to a disruption of Ca2+ homeostasis in cardiac myocytes that results in arrhythmias. We discuss evidence supporting the hypothesis that mutations in each of these situations alter protein/protein interactions within the RyR complex or between the RyR and its associated proteins. The disruption of these protein-protein interactions can lead either to excess Ca2+ release or reduced Ca2+ release and thus to abnormal Ca2+ homeostasis. Much of the evidence for disruption of protein-protein interactions has been provided by the actions of a group of novel RyR regulators, domain peptides with sequences that correspond to sequences within the RyR and which compete with the endogenous residues for their interaction sites.
authors.affiliation: Division of Molecular Bioscience, JCSMR and RSC, ANU, Canberra, ACT, 2601, Australia. angela.dulhunty@anu.edu.au
authors.forename: A F
authors.initials: AF
authors.lastname: Dulhunty
authors.forename: N A
authors.initials: NA
authors.lastname: Beard
authors.forename: P
authors.initials: P
authors.lastname: Pouliquin
authors.forename: T
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002118:Calcium / Q000378:metabolism; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism; D009135:Muscular Diseases / Q000209:etiology* / Q000503:physiopathology; D009154:Mutation; D010455:Peptides / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D002155:Calsequestrin; D010455:Peptides; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium