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  • Title: Dihydropyridine receptors actively control gating of ryanodine receptors in resting mouse skeletal muscle fibres.
    Author: Robin G, Allard B.
    Journal: J Physiol; 2012 Dec 01; 590(23):6027-36. PubMed ID: 23006480.
    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.
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