A malignant hyperthermia-inducing mutation in RYR1 (R163C): Consequent alterations in the functional properties of DHPR channels

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

Research output: Contribution to journalArticle

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Abstract

Bidirectional communication between the 1,4-dihydropyridine receptor (DHPR) in the plasma membrane and the type 1 ryanodine receptor (RYR1) in the sarcoplasmic reticulum (SR) is responsible for both skeletal-type excitation-contraction coupling (voltage-gated Ca2+ release from the SR) and increased amplitude of L-type Ca2+ current via the DHPR. Because the DHPR and RYR1 are functionally coupled, mutations in RYR1 that are linked to malignant hyperthermia (MH) may affect DHPR activity. For this reason, we investigated whether cultured myotubes originating from mice carrying an MH-linked mutation in RYR1 (R163C) had altered voltage-gated Ca2+ release from the SR, membrane-bound charge movement, and/or L-type Ca 2+ current. In myotubes homozygous (Horn) for the R163C mutation, voltage-gated Ca2+ release from the SR was substantially reduced and shifted (∼10 mV) to more hyperpolarizing potentials compared with wild-type (WT) myotubes. Intramembrane charge movements of both Hom and heterozygous (Het) myotubes displayed hyperpolarizing shifts similar to that observed in voltagegated SR Ca2+ release. The current-voltage relationships for L-type currents in both Hom and Het myotubes were also shifted to more hyperpolarizing potentials (∼7 and 5 mV, respectively). Compared with WT myotubes, Het and Horn myotubes both displayed a greater sensitivity to the L-type channel agonist ±Bay K 8644 (10 μM). In general, L-type currents in WT, Het, and Hom myotubes inactivated modesdy after 30-s prepulses to -50, -10, 0, 10, 20, and 30 mV. However, L-type currents in Hom myotubes displayed a hyperpolarizing shift in inactivation relative to L-type currents in either WT or Het myotubes. Our present results indicate that mutations in RYR1 can alter DHPR activity and raise the possibility that this altered DHPR function may contribute to MH episodes.

Original languageEnglish (US)
Pages (from-to)629-640
Number of pages12
JournalJournal of General Physiology
Volume135
Issue number6
DOIs
StatePublished - Jun 2010

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Malignant Hyperthermia
L-Type Calcium Channels
Skeletal Muscle Fibers
Mutation
Sarcoplasmic Reticulum
Horns
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Excitation Contraction Coupling
Ryanodine Receptor Calcium Release Channel
Communication
Cell Membrane

ASJC Scopus subject areas

  • Physiology

Cite this

A malignant hyperthermia-inducing mutation in RYR1 (R163C) : Consequent alterations in the functional properties of DHPR channels. / Bannister, Roger A.; Estève, Eric; Eltit, José M.; Pessah, Isaac N; Allen, Paul D.; López, José R.; Beam, Kurt G.

In: Journal of General Physiology, Vol. 135, No. 6, 06.2010, p. 629-640.

Research output: Contribution to journalArticle

Bannister, Roger A. ; Estève, Eric ; Eltit, José M. ; Pessah, Isaac N ; Allen, Paul D. ; López, José R. ; Beam, Kurt G. / A malignant hyperthermia-inducing mutation in RYR1 (R163C) : Consequent alterations in the functional properties of DHPR channels. In: Journal of General Physiology. 2010 ; Vol. 135, No. 6. pp. 629-640.
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