Source:http://linkedlifedata.com/resource/pubmed/id/21289290
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rdf:type | |
lifeskim:mentions |
umls-concept:C0006772,
umls-concept:C0030685,
umls-concept:C0036226,
umls-concept:C0054493,
umls-concept:C0221099,
umls-concept:C0242692,
umls-concept:C0391871,
umls-concept:C0596235,
umls-concept:C0680255,
umls-concept:C0851285,
umls-concept:C1283071,
umls-concept:C1419781,
umls-concept:C1709059,
umls-concept:C1963578
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pubmed:issue |
5
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pubmed:dateCreated |
2011-4-27
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pubmed:abstractText |
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.
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pubmed:grant |
http://linkedlifedata.com/resource/pubmed/grant/AR018687,
http://linkedlifedata.com/resource/pubmed/grant/AR053235,
http://linkedlifedata.com/resource/pubmed/grant/AR055099,
http://linkedlifedata.com/resource/pubmed/grant/AR059179,
http://linkedlifedata.com/resource/pubmed/grant/GM58888,
http://linkedlifedata.com/resource/pubmed/grant/HL081825
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pubmed:commentsCorrections | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Calmodulin,
http://linkedlifedata.com/resource/pubmed/chemical/Ryanodine Receptor Calcium Release...,
http://linkedlifedata.com/resource/pubmed/chemical/S100 Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/S100A1 protein
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1522-1563
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pubmed:author |
pubmed-author:CannonBrian RBR,
pubmed-author:EuJerry PJP,
pubmed-author:GhassemiFarshidF,
pubmed-author:Hernández-OchoaErick OEO,
pubmed-author:LinN GNG,
pubmed-author:LoveringRichard MRM,
pubmed-author:MeissnerGerhardG,
pubmed-author:MelzerWernerW,
pubmed-author:PasekDaniel ADA,
pubmed-author:ProsserBenjamin LBL,
pubmed-author:SchneiderMartin FMF,
pubmed-author:WeberDavidD,
pubmed-author:WilderPaul TPT,
pubmed-author:YamaguchiNaohiroN
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pubmed:issnType |
Electronic
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pubmed:volume |
300
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
C998-C1012
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pubmed:meshHeading |
pubmed-meshheading:21289290-Action Potentials,
pubmed-meshheading:21289290-Animals,
pubmed-meshheading:21289290-Calcium,
pubmed-meshheading:21289290-Calmodulin,
pubmed-meshheading:21289290-Female,
pubmed-meshheading:21289290-Male,
pubmed-meshheading:21289290-Mice,
pubmed-meshheading:21289290-Muscle, Skeletal,
pubmed-meshheading:21289290-Muscle Contraction,
pubmed-meshheading:21289290-Muscle Strength,
pubmed-meshheading:21289290-Protein Binding,
pubmed-meshheading:21289290-Ryanodine Receptor Calcium Release Channel,
pubmed-meshheading:21289290-S100 Proteins,
pubmed-meshheading:21289290-Sarcoplasmic Reticulum
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pubmed:year |
2011
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pubmed:articleTitle |
Modulation of sarcoplasmic reticulum Ca2+ release in skeletal muscle expressing ryanodine receptor impaired in regulation by calmodulin and S100A1.
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pubmed:affiliation |
Dept. of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-7260, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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