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Alteration of intracellular Ca2+ in COS-7 cells transfected with the cDNA encoding skeltal muscle ryanodine receptor carrying a mutation associated with malignant hyperthermia

By S. TREVES, F. LARINI, P. MENEGAZZI, T.H. STEINBERG, M. KOVAL, B. VILSEN, J.P. ANDERSEN and F. ZORZATO

Abstract

Malignant hyperthermia (MH), an inherited neuromuscular disease triggered by halogenated inhalational anaesthetics and skeletal-muscle relaxants, appears to be due to an alteration of intracellular Ca2+ homoeostasis. MH occurs in 1 out of 20,000 anaesthetized adults and is characterized by hypermetabolism, skeletal-muscle rigidity and elevation in body temperature, which is frequently fatal [MacLennan and Phillips (1992) Science 256, 789-794]. The defect responsible for the disease may lie within the mechanism controlling the release of Ca2+ from sarcoplasmic reticulum via the ryanodine-receptor (RYR) Ca2+ channel; in fact a point mutation in the RYR has been associated with MH in some human families, as well as in the MH-susceptible pig. To date, however, no direct evidence has been obtained demonstrating that the point mutation is both necessary and sufficient to cause functional alterations in RYR-mediated Ca2+ release. In the present report we show that the presence of the Arg-to-Cys point mutation in the recombinant RYR expressed in COS-7 transfected cells causes abnormal cytosolic Ca2+ transients in response to 4-chloro-m-cresol, an agent capable of eliciting in vitro contracture of MH-susceptible muscle

Topics: expression recombintat ryanodien receptor, mutation
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Year: 1994
OAI identifier: oai:iris.unife.it:11392/463583
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