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J. Biol. Chem., Vol. 283, Issue 34, 23217-23223, August 22, 2008

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The _1S III-IV Loop Influences 1,4-Dihydropyridine Receptor Gating but Is Not Directly Involved in Excitation-Contraction Coupling Interactions with the Type 1 Ryanodine Receptor^*

Roger A. Bannister¹, Manfred Grabner, and Kurt G. Beam²

From the Department of Physiology and Biophysics, University of Colorado-Denver, Aurora, Colorado 80045 and the Department of Medical Genetics, Clinical and Molecular Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria

In skeletal muscle, coupling between the 1,4-dihydropyridine receptor (DHPR) and the type 1 ryanodine receptor (RyR1) underlies excitation-contraction (EC) coupling. The III-IV loop of the DHPR _1S subunit binds to a segment of RyR1 in vitro, and mutations in the III-IV loop alter the voltage dependence of EC coupling, raising the possibility that this loop is directly involved in signal transmission from the DHPR to RyR1. To clarify the role of the _1S III-IV loop in EC coupling, we examined the functional properties of a chimera (GFP-_1S[III-IVa]) in which the III-IV loop of the divergent _1A isoform replaced that of _1S. Dysgenic myotubes expressing GFP-_1S[III-IVa] yielded myoplasmic Ca²⁺ transients that activated at 10 mV more hyperpolarized potentials and that were 65% smaller than those of GFP-_1S. A similar reduction was observed in voltage-dependent charge movements for GFP-_1S[III-IVa], indicating that the chimeric channels trafficked less well to the membrane but that those that were in the membrane functioned as efficiently in EC coupling as GFP-_1S. Relative to GFP-_1S, L-type currents mediated by GFP-_1S[III-IVa] were 40% smaller and activated at 5 mV more hyperpolarized potentials. The altered gating of GFP-_1S[III-IVa] was accentuated by exposure to ±Bay K 8644, which caused a much larger hyperpolarizing shift in activation compared with its effect on GFP-_1S. Taken together, our observations indicate that the _1S III-IV loop is not directly involved in EC coupling but does influence DHPR gating transitions important both for EC coupling and activation of L-type conductance.

Received for publication, June 4, 2008 , and in revised form, June 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants NS24444 and AR44750 (to K. G. B.). This work was also supported by Fonds zur Förderung der wissenschaftlichen Forschung Grant P16098 [GenBank] -B04 (to M. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Muscular Dystrophy Association Developmental Grant MDA4155.

² To whom correspondence should be addressed: Dept. of Physiology and Biophysics, University of Colorado-Denver, P.O. Box 6511, Mail Stop F8307, Aurora, CO 80045. Tel.: 303-724-4542; Fax: 303-724-4501; E-mail: kurt.beam{at}uchsc.edu.

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