A malignant hyperthermia-inducing mutation in RYR1 (R163C): Alterations in Ca2+ entry, release, and retrograde signaling to the DHPR

Eric Estève, José M. Eltit, Roger A. Bannister, Isaac N Pessah, Kurt G. Beam, Paul D. Allen, José R. López

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Bidirectional signaling between the sarcolemmal L-type Ca2+ channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca2+ release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation-contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Horn) RYR1-R163C knock-in mouse myotubes to maintained KT depolarization. The new findings are: (a) For all there genotypes, Ca2+ transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT > Het > Horn, (c) The removal of external Ca2+ or the addition of Ca2+ entry blockers (nifedipine, SKF96365, and Ni2+) enhanced the rate of decay in all genotypes, (d) When Ca2+ entry is blocked, die decay rates are slower for Horn and Het than WT, indicating that the rate of inactivation of ECC is affected by the R163C mutation and is genotype dependent (WT > Het > Horn), (e) Reduced ECC inactivation in Het and Horn myotubes was shown directly using two identical K+ depolarizations separated by varying time intervals. These data suggest that conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor

Original languageEnglish (US)
Pages (from-to)619-628
Number of pages10
JournalJournal of General Physiology
Volume135
Issue number6
DOIs
StatePublished - Jun 2010

ASJC Scopus subject areas

  • Physiology

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