University of Heidelberg (2006) Proc Physiol Soc 4, SA4
Research Symposium: Angela F. Dulhunty1, N. Beard1, P. Pouliquin1, T. Kimura1
1. Division of Molecular Bioscience, Australian National University, Canberra, ACT, Australia.
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 RyR1 have been identified and linked to malignant hyperthermia, central core disease or multi-minicore disease, while more than 40 mutations in RyR2 lead to ventricular arrhythmias and sudden cardiac death. These RyR mutations cause diverse changes in RyR activity which either excessively activate or block the channel in a manner that disrupts Ca2+ signalling. There are two regions of RyR1 that are variably spiced and developmentally regulated (ASI and ASII). In myotonic dystrophy (DM), the less active juvenile isoform of the skeletal RyR, ASI(-), is preferentially expressed in adults and may contribute to functional changes in the dystrophic muscle. 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 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.
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