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Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1.
- Source :
- American Journal of Physiology: Cell Physiology; May2011, Vol. 300 Issue 5, pC998-C1012, 15p
- Publication Year :
- 2011
-
Abstract
- In vitro, calmodulin (CaM) and S100A1 activate the skeletal muscle ryanodine receptor ion channel (RyR1) at submicromolar Ca<superscript>2+</superscript> concentrations, whereas at micromolar Ca<superscript>2+</superscript> 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<superscript>D/D</superscript>) were viable and appeared normal. However, single RyR1 channel recordings from Ryr1<superscript>D/D</superscript> mice exhibited impaired activation by CaM and S100A1 and impaired CaCaM inhibition. Isolated flexor digitorum brevis muscle fibers from Ryr1<superscript>D/D</superscript> mice had depressed Ca<superscript>2+</superscript> transients when stimulated by a single action potential. However, during repetitive stimulation, the mutant fibers demonstrated greater relative summation of the Ca<superscript>2+</superscript> transients. Consistently, in vivo stimulation of tibialis anterior muscles in Ryr1<superscript>D/D</superscript> 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<superscript>D/D</superscript> fibers exhibited slowed inactivation of sarcoplasmic reticulum Ca<superscript>2+</superscript> release flux, consistent with increased summation of the Ca<superscript>2+</superscript> transient and contractile force. Peak Ca<superscript>2+</superscript> release flux was suppressed at all voltages in voltage-clamped Ryr1<superscript>D/D</superscript> 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<superscript>2+</superscript> release, providing new insights into CaM and S100A1 regulation of skeletal muscle excitation-contraction coupling. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03636143
- Volume :
- 300
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- American Journal of Physiology: Cell Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 64373679
- Full Text :
- https://doi.org/10.1152/ajpcell.00370.2010