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Ryanodine modification of RyR1 retrogradely affects L-type Ca2+ channel gating in skeletal muscle

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Abstract

In skeletal muscle, there is bidirectional signalling between the L-type Ca2+ channel (1,4-dihydropyridine receptor; DHPR) and the type 1 ryanodine-sensitive Ca2+ release channel (RyR1) of the sarcoplasmic reticulum (SR). In the case of “orthograde signalling” (i.e., excitation-contraction coupling), the conformation of RyR1 is controlled by depolarization-induced conformational changes of the DHPR resulting in Ca2+ release from the SR. “Retrograde coupling” is manifested as enhanced L-type current. The nature of this retrograde signal, and its dependence on RyR1 conformation, are poorly understood. Here, we have examined L-type currents in normal myotubes after an exposure to ryanodine (200 μM, 1 h at 37°C) sufficient to lock RyR1 in a non-conducting, inactivated, conformational state. This treatment caused an increase in L-type current at less depolarized test potentials in comparison to myotubes similarly exposed to vehicle as a result of a ~5 mV hyperpolarizing shift in the voltage-dependence of activation. Charge movements of ryanodine-treated myotubes were also shifted to more hyperpolarizing potentials (~13 mV) relative to vehicle-treated myotubes. Enhancement of the L-type current by ryanodine was absent in dyspedic (RyR1 null) myotubes, indicating that ryanodine does not act directly on the DHPR. Our findings indicate that in retrograde signaling, the functional state of RyR1 influences conformational changes of the DHPR involved in activation of L-type current. This raises the possibility that physiological regulators of the conformational state of RyR1 (e.g., Ca2+, CaM, CaMK, redox potential) may also affect DHPR gating.

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Abbreviations

DHPR:

1,4-dihydropyridine receptor

EC:

Excitation–contraction

RyR:

Ryanodine-sensitive intracellular Ca2+ release channel

SR:

Sarcoplasmic reticulum

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Acknowledgments

We thank Dr. D.C. Sheridan and Mr. J.D. Ohrtman for insightful discussion. This work was supported in part by National Institutes of Health Grants NS24444 and AR44750 (to K.G.B.). R.A.B. was supported by a Developmental Grant from Muscular Dystrophy Association (MDA4155).

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  1. Department of Physiology and Biophysics, School of Medicine, University of Colorado-Denver, RC-1, North Tower, P18-7130, Mail Stop F8307, PO Box 6511, Aurora, CO, 80045, USA

    R. A. Bannister & K. G. Beam

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  1. R. A. Bannister
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  2. K. G. Beam
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Correspondence to R. A. Bannister.

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Bannister, R.A., Beam, K.G. Ryanodine modification of RyR1 retrogradely affects L-type Ca2+ channel gating in skeletal muscle. J Muscle Res Cell Motil 30, 217–223 (2009). https://doi.org/10.1007/s10974-009-9190-0

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  • DOI: https://doi.org/10.1007/s10974-009-9190-0

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