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J Physiol. 2012 Dec 1;590(23):6027-36. doi: 10.1113/jphysiol.2012.237321. Epub 2012 Sep 24.

Dihydropyridine receptors actively control gating of ryanodine receptors in resting mouse skeletal muscle fibres.

Author information

1
Université Lyon 1, CNRS UMR 5534, Centre de Génétique et de Physiologie Moléculaires et Cellulaires, 43 boulevard du 11 novembre 1918, 69622 Villeurbanne cedex, France.

Abstract

Contraction of skeletal muscle is triggered by the release of Ca(2+) from the sarcoplasmic reticulum (SR) in response to depolarization of the muscle membrane. Depolarization is known to elicit a conformational change of the dihydropyridine receptor (DHPR) in the tubular membrane that controls in a time- and voltage-dependent manner the opening of the ryanodine receptor (RyR), the SR Ca(2+) release channel. At rest, it is assumed that RyRs are kept in a closed state imposed by the repressive action of DHPRs; however, a direct control of the RyR gating by the DHPR has up to now never been demonstrated in resting adult muscle. In this study, we monitored slow changes in SR Ca(2+) content using the Ca(2+) indicator fluo-5N loaded in the SR of voltage-clamped mouse muscle fibres. We first show that external Ca(2+) removal induced a reversible SR Ca(2+) efflux at -80 mV and prevented SR Ca(2+) refilling following depolarization-evoked SR Ca(2+) depletion. The dihydropyridine compound nifedipine induced similar effects. The rate of SR Ca(2+) efflux was also shown to be controlled in a time- and voltage-dependent manner within a membrane potential range more negative than -50 mV. Finally, intracellular addition of ryanodine produced an irreversible SR Ca(2+) efflux and kept the SR in a highly depleted state following depolarization-evoked SR Ca(2+) depletion. The fact that resting SR Ca(2+) efflux is modulated by conformational changes of DHPRs induced by external Ca(2+), nifedipine and voltage demonstrates that DHPRs exert an active control on gating of RyRs in resting skeletal muscle.

PMID:
23006480
PMCID:
PMC3530114
DOI:
10.1113/jphysiol.2012.237321
[Indexed for MEDLINE]
Free PMC Article

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