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Am J Physiol Cell Physiol 287: C1094-C1102, 2004. First published June 16, 2004; doi:10.1152/ajpcell.00173.2004
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RECEPTORS AND SIGNAL TRANSDUCTION

Functional analysis of the R1086H malignant hyperthermia mutation in the DHPR reveals an unexpected influence of the III-IV loop on skeletal muscle EC coupling

Regina G. Weiss,1 Kristen M. S. O’Connell,2 Bernhard E. Flucher,3 Paul D. Allen,4 Manfred Grabner,1 and Robert T. Dirksen2

Departments of 1Biochemical Pharmacology and 3Physiology, Innsbruck Medical University, A-6020 Innsbruck, Austria; 2Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642; and 4Department of Anesthesia Research, Brigham and Women’s Hospital, Boston, Massachusetts 02115

Submitted 1 April 2004 ; accepted in final form 8 June 2004

Malignant hyperthermia (MH) is an inherited pharmacogenetic disorder caused by mutations in the skeletal muscle ryanodine receptor (RyR1) and the dihydropyridine receptor (DHPR) {alpha}1S-subunit. We characterized the effects of an MH mutation in the DHPR cytoplasmic III-IV loop of {alpha}1S (R1086H) on DHPR-RyR1 coupling after reconstitution in dysgenic ({alpha}1S null) myotubes. Compared with wild-type {alpha}1S, caffeine-activated Ca2+ release occurred at approximately fivefold lower concentrations in nonexpressing and R1086H-expressing myotubes. Although maximal voltage-gated Ca2+ release was similar in {alpha}1S- and R1086H-expressing myotubes, the voltage dependence of Ca2+ release was shifted ~5 mV to more negative potentials in R1086H-expressing myotubes. Our results demonstrate that {alpha}1S functions as a negative allosteric modulator of release channel activation by caffeine/voltage and that the R1086H MH mutation in the intracellular III-IV linker disrupts this negative regulatory influence. Moreover, a low caffeine concentration (2 mM) caused a similar shift in voltage dependence of Ca2+ release in {alpha}1S- and R1086H-expressing myotubes. Compared with {alpha}1S-expressing myotubes, maximal L channel conductance (Gmax) was reduced in R1086H-expressing myotubes ({alpha}1S 130 ± 10.2, R1086H 88 ± 6.8 nS/nF; P < 0.05). The decrease in Gmax did not result from a change in retrograde coupling with RyR1 as maximal conductance-charge movement ratio (Gmax/Qmax) was similar in {alpha}1S- and R1086H-expressing myotubes and a similar decrease in Gmax was observed for an analogous mutation engineered into the cardiac L channel (R1217H). In addition, both R1086H and R1217H DHPRs targeted normally and colocalized with RyR1 in sarcoplasmic reticulum (SR)-sarcolemmal junctions. These results indicate that the R1086H MH mutation in {alpha}1S enhances RyR1 sensitivity to activation by both endogenous (voltage sensor) and exogenous (caffeine) activators.

excitation-contraction coupling; calcium channel; muscle disease


Address for reprint requests and other correspondence: M. Grabner, Dept. of Biochemical Pharmacology, Innsbruck Medical Univ., Peter-Mayr-Strasse 1, A-6020 Innsbruck, Austria (E-mail: manfred.grabner{at}uibk.ac.at)




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