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

Abstract

Key points• Depolarization of the skeletal muscle membrane elicits a change in the configuration of dihydropyridine receptors that in turn triggers sarcoplasmic reticulum (SR) Ca 2+ release through ryanodine receptors.• At rest, it is assumed, but never demonstrated in adult muscle fibres, that dihydropyridine receptors exert a repressive action on ryanodine receptors that keeps them in a closed state.• By measuring Ca 2+ changes in the SR in voltage-clamp conditions, we report that any interventions designed to alter the conformation of dihydropyridine receptors at rest induce an SR Ca 2+ efflux.• These results show that dihydropyridine receptors maintain a strict control upon ryanodine receptors in resting skeletal mouse muscle fibres.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.

Ca2+ leakage out of the sarcoplasmic reticulum is increased in type I skeletal muscle fibres in aged humans

“…; Eltit et al . ; Robin & Allard, ). However, in the human tissue in the present study, we found no evidence of a differential loss of DHPRs or indeed of any overall loss of either DHPRs or RyRs in the muscle of the Old subjects; on average, the density of the DHPRs and RyRs in total muscle homogenates from the 11 Old subjects was ∼0.98 and ∼0.96 times, respectively, of that found in the muscle of the 10 Young subjects (Table ).…”

“…We also examined the densities of both the DHPR α1 subunits and the RyRs in the muscle of the Old relative to the Young subjects because it has been reported that there is a loss of DHPRs with age in rodent and rabbit muscle (Renganathan et al 1997;Ryan et al 2000). It has been suggested that such a loss of DHPRs underlies the decreased SR Ca 2+ release seen in both rodent (Wang et al 2000) and human muscle (Delbono et al 1995) and it might also increase SR Ca 2+ leakage because of a decrease in the resting inhibition exerted by the DHPRs on the RyRs (Zhou et al 2006;Eltit et al 2011;Robin & Allard, 2012). However, in the human tissue in the present study, we found no evidence of a differential loss of DHPRs or indeed of any overall loss of either DHPRs or RyRs in the muscle of the Old subjects; on average, the density of the DHPRs and RyRs in total muscle homogenates from the 11 Old subjects was ß0.98 and ß0.96 times, respectively, of that found in the muscle of the 10 Young subjects (Table 2).…”

The cost of muscle power production: muscle oxygen consumption per unit work increases at low temperatures inXenopus laevisDaudin

“…A likely explanation for the differences in response between swimming and isolated muscle performance is that short bursts of locomotion rely on creatine kinase dynamics to supply ATP and are therefore independent from oxygen consumption, at least in the short term (Gray et al, 2006;Wüst et al, 2013). Additionally, it is possible that burst performance may rely more on the excitation of the muscle rather than on muscle contraction-relaxation dynamics (Robin and Allard, 2012) so that it is more dependent on neural signal transmission than on muscle function per se.…”

Review of RyR1 pathway and associated pathomechanisms

“…DHPRs are located in the transverse tubule of skeletal muscle clustered in tetrads. Each tetrad interacts with every other RyR1 homotetramer [116], and is activated by sarcolemmal depolarization [31, 116]. Once activated, DHPRs undergo a conformational change that leads to RyR1-mediated Ca ++ release [105, 116].…”