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Molecular Pharmacology

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Research ArticleArticle

Functional and Biochemical Properties of Ryanodine Receptor Type 1 Channels from Heterozygous R163C Malignant Hyperthermia-Susceptible Mice

Wei Feng, Genaro C. Barrientos, Gennady Cherednichenko, Tianzhong Yang, Isela T. Padilla, Kim Truong, Paul D. Allen, José R. Lopez and Isaac N. Pessah
Molecular Pharmacology March 2011, 79 (3) 420-431; DOI: https://doi.org/10.1124/mol.110.067959
Wei Feng
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Genaro C. Barrientos
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Gennady Cherednichenko
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Tianzhong Yang
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Isela T. Padilla
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Kim Truong
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Paul D. Allen
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José R. Lopez
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Isaac N. Pessah
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Abstract

Mutations in ryanodine receptor type 1 (RyR1) confer malignant hyperthermia susceptibility. How inherent impairments in Ca2+ channel regulation affect skeletal muscle function in myotubes and adult fibers under basal (nontriggering) conditions are not understood. Myotubes, adult flexor digitorum brevis (FDB) fibers, and sarcoplasmic reticulum skeletal membranes were isolated from heterozygous knockin R163C and wild-type (WT) mice. Compared with WT myotubules, R163C myotubes have reduced Ca2+ transient amplitudes in response to electrical field pulses; however, R163C FDB fibers do not differ in their responses to electrical stimuli, despite heightened cellular cytoplasmic resting Ca2+ ([Ca2+]rest) and sensitivity to halothane. Immunoblotting of membranes from each genotype shows similar expression of RyR1, FK506 binding protein 12 kDa, and Ca2+-ATPase, but RyR1 2844Ser phosphorylation in R163C muscle is 31% higher than that of WT muscle (p < 0.001). RyR1 channels reconstituted in planar lipid bilayers reveal ∼65% of R163C channels exhibit ≥2-fold greater open probability (Po) than WT, with prolonged mean open dwell times and shortened closed dwell times. [3H]Ryanodine (Ry) binding and single-channel analyses show that R163C-RyR1 has altered regulation compared with WT: 1) 3-fold higher sensitivity to Ca2+ activation; 2) 2-fold greater [3H]Ry receptor occupancy; 3) comparatively higher channel activity, even in reducing glutathione buffer; 4) enhanced RyR1 activity both at 25 and 37°C; and 5) elevated cytoplasmic [Ca2+]rest. R163C channels are inherently more active than WT channels, a functional impairment that cannot be reversed by dephosphorylation with protein phosphatase. Dysregulated R163C channels produce a more overt phenotype in myotubes than in adult fibers in the absence of triggering agents, suggesting tighter negative regulation of R163C-RyR1 within the Ca2+ release unit of adult fibers.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Arthritis and Musculoskeletal and Skin Disease [Grants AR46513, AR52354]; and the National Institute of Environmental Health Sciences [Grants ES014901, ES04699].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.067959.

  • ABBREVIATIONS:

    MH
    malignant hyperthermia
    MHS
    malignant hyperthermia susceptibility
    RyR1
    ryanodine receptor type 1
    SR
    sarcoplasmic reticulum
    EC
    excitation-contraction
    [Ca2+]rest
    cellular cytoplasmic resting Ca2+
    DHPR
    dihydropyridine receptor
    CRU
    Ca2+ release unit
    WT
    wild type
    ECCE
    excitation-coupled calcium entry
    FDB
    flexor digitorum brevis
    F
    fluorescence
    PAGE
    polyacrylamide gel electrophoresis
    SERCA
    sarcoplasmic reticulum/endoplasmic reticulum calcium ATPase
    FKBP12
    FK506 binding protein 12 kDa
    PP1
    protein phosphatase 1
    Ry
    ryanodine
    TG
    thapsigargin
    GSH
    glutathione
    GSSH
    oxidized glutathione
    BLM
    bilayer lipid membrane
    P-
    phosphorylated.

  • Received August 1, 2010.
  • Accepted December 14, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (3)
Molecular Pharmacology
Vol. 79, Issue 3
1 Mar 2011
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Research ArticleArticle

Functional and Biochemical Properties of Ryanodine Receptor Type 1 Channels from Heterozygous R163C Malignant Hyperthermia-Susceptible Mice

Wei Feng, Genaro C. Barrientos, Gennady Cherednichenko, Tianzhong Yang, Isela T. Padilla, Kim Truong, Paul D. Allen, José R. Lopez and Isaac N. Pessah
Molecular Pharmacology March 1, 2011, 79 (3) 420-431; DOI: https://doi.org/10.1124/mol.110.067959

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Research ArticleArticle

Functional and Biochemical Properties of Ryanodine Receptor Type 1 Channels from Heterozygous R163C Malignant Hyperthermia-Susceptible Mice

Wei Feng, Genaro C. Barrientos, Gennady Cherednichenko, Tianzhong Yang, Isela T. Padilla, Kim Truong, Paul D. Allen, José R. Lopez and Isaac N. Pessah
Molecular Pharmacology March 1, 2011, 79 (3) 420-431; DOI: https://doi.org/10.1124/mol.110.067959
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