Abstract In vitro, calmodulin (CaM) and S100A1 activate the skeletal muscle ryanodine receptor ion channel (RyR1) at submicromolar Ca 2+ concentrations, whereas at micromolar Ca 2+ concentrations, CaM inhibits RyR1. One amino acid substitution (RyR1-L3625D) has previously been demonstrated to impair CaM binding and regulation of RyR1. Here we show that the RyR1-L3625D substitution also abolishes S100A1 binding. To determine the physiological relevance of these findings, mutant mice were generated with the RyR1-L3625D substitution in exon 74, which encodes the CaM and S100A1 binding domain of RyR1. Homozygous mutant mice ( Ryr1 D/D ) were viable and appeared normal. However, single RyR1 channel recordings from Ryr1 D/D mice exhibited impaired activation by CaM and S100A1 and impaired CaCaM inhibition. Isolated flexor digitorum brevis muscle fibers from Ryr1 D/D mice had depressed Ca 2+ transients when stimulated by a single action potential. However, during repetitive stimulation, the mutant fibers demonstrated greater relative summation of the Ca 2+ transients. Consistently, in vivo stimulation of tibialis anterior muscles in Ryr1 D/D mice demonstrated reduced twitch force in response to a single action potential, but greater summation of force during high-frequency stimulation. During repetitive stimulation, Ryr1 D/D fibers exhibited slowed inactivation of sarcoplasmic reticulum Ca 2+ release flux, consistent with increased summation of the Ca 2+ transient and contractile force. Peak Ca 2+ release flux was suppressed at all voltages in voltage-clamped Ryr1 D/D fibers. The results suggest that the RyR1-L3625D mutation removes both an early activating effect of S100A1 and CaM and delayed suppressing effect of CaCaM on RyR1 Ca 2+ release, providing new insights into CaM and S100A1 regulation of skeletal muscle excitation-contraction coupling. Ca 2+ release channel excitation-contraction coupling Ryr1 D/D mouse RyR1-L3625D Footnotes Copyright © 2011 the American Physiological Society
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Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1
Yamaguchi, Naohiro; Prosser, Benjamin L.; Ghassemi, Farshid; Xu, Le; Pasek, Daniel A.; Eu, Jerry P.; Hernández-Ochoa, Erick O.; Cannon, Brian R.; Wilder, Paul T.; Lovering, Richard M.; Weber, David; Melzer, Werner; Schneider, Martin F.; Meissner, Gerhard
Follow AJP - Cell Physiology
, Volume 300 (5): C998
The American Physiological Society – May 1, 2011
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