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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/C1103    most recent ajpcell.90642.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Diaz-Sylvester, P. L. Articles by Copello, J. A. PubMed PubMed Citation Articles by Diaz-Sylvester, P. L. Articles by Copello, J. A.

MUSCLE CELL BIOLOGY AND CELL MOTILITY

Halothane modulation of skeletal muscle ryanodine receptors: dependence on Ca²⁺, Mg²⁺, and ATP

¹Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois; ²Department of Physiology, Loyola University Chicago, Maywood, Illinois

Submitted 19 December 2007 ; accepted in final form 25 February 2008

Malignant hyperthermia (MH) susceptibility is a genetic disorder of skeletal muscle associated with mutations in the ryanodine receptor isoform 1 (RyR1) of sarcoplasmic reticulum (SR). In MH-susceptible skeletal fibers, RyR1-mediated Ca²⁺ release is highly sensitive to activation by the volatile anesthetic halothane. Indeed, studies with isolated RyR1 channels (using simple Cs⁺ solutions) found that halothane selectively affects mutated but not wild-type RyR1 function. However, studies in skeletal fibers indicate that halothane can also activate wild-type RyR1-mediated Ca²⁺ release. We hypothesized that endogenous RyR1 agonists (ATP, lumenal Ca²⁺) may increase RyR1 sensitivity to halothane. Consequently, we studied how these agonists affect halothane action on rabbit skeletal RyR1 reconstituted into planar lipid bilayers. We found that cytosolic ATP is required for halothane-induced activation of the skeletal RyR1. Unlike RyR1, cardiac RyR2 (much less sensitive to ATP) responded to halothane even in the absence of this agonist. ATP-dependent halothane activation of RyR1 was enhanced by cytosolic Ca²⁺ (channel agonist) and counteracted by Mg²⁺ (channel inhibitor). Dantrolene, a muscle relaxant used to treat MH episodes, did not affect RyR1 or RyR2 basal activity and did not interfere with halothane-induced activation. Studies with skeletal SR microsomes confirmed that halothane-induced RyR1-mediated SR Ca²⁺ release is enhanced by high ATP-low Mg²⁺ in the cytosol and by increased SR Ca²⁺ load. Thus, physiological or pathological processes that induce changes in cellular levels of these modulators could affect RyR1 sensitivity to halothane in skeletal fibers, including the outcome of halothane-induced contracture tests used to diagnose MH susceptibility.

volatile anesthetics; dantrolene; sarcoplasmic reticulum; excitation-contraction coupling; malignant hyperthermia