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JP-45/JSRP1 Variants Affect Skeletal Muscle Excitation–Contraction Coupling by Decreasing the Sensitivity of the Dihydropyridine Receptor

Authors

  • Toshimichi Yasuda,

    1. Department of Anesthesiology and Critical Care, Hiroshima University, Manami-ku, Hiroshima, Japan
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  • Osvaldo Delbono,

    1. Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina
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  • Zhong-Min Wang,

    1. Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina
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  • Maria L. Messi,

    1. Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina
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  • Thierry Girard,

    1. Departments of Anesthesia and Biomedizin, Basel University Hospital, Basel, Switzerland
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  • Albert Urwyler,

    1. Departments of Anesthesia and Biomedizin, Basel University Hospital, Basel, Switzerland
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  • Susan Treves,

    Corresponding author
    1. Department of Experimental and Diagnostic Medicine, General Pathology Section, University of Ferrara, Ferrara, Italy
    • Departments of Anesthesia and Biomedizin, Basel University Hospital, Basel, Switzerland
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  • Francesco Zorzato

    1. Departments of Anesthesia and Biomedizin, Basel University Hospital, Basel, Switzerland
    2. Department of Experimental and Diagnostic Medicine, General Pathology Section, University of Ferrara, Ferrara, Italy
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  • Communicated by Jürgen Horst

  • Contract grant sponsors: Department of Anesthesia, Basel University Hospital; Swiss National Science Foundation (SNF 310030-129785); Association Française contre les Myopathies (AFM); National Institutes of Health (grants AG13934 and AG15820); Japan Society for the Promotion of Science (No. 23592291); Wake Forest University Pepper Older Americans Independence Center (P30-AG21332).

Correspondence to: Susan Treves, Basel University Hospital, Anesthesia and Research, Hebelstrasse 20, Basel, 4031, Switzerland. E-mail: susan.treves@unibas.ch

ABSTRACT

JP-45 (also JP45; encoded by JSRP1) is an integral protein constituent of the skeletal muscle sarcoplasmic reticulum junctional face membrane interacting with Cav1.1 (the α.1 subunit of the voltage-sensing dihydropyridine receptor, DHPR) and the luminal calcium-binding protein calsequestrin. Two JSRP1 variants have been found in the human population: c.323C>T (p.P108L) in exon 5 and c.449G>C (p.G150A) in exon 6, but nothing is known concerning the incidence of these polymorphisms in the general population or in patients with neuromuscular diseases nor the impact of the polymorphisms on excitation–contraction (EC) coupling. In the present report, we investigated the frequencies of these two JSRP1 polymorphisms in the Swiss malignant hyperthermia population and studied the functional impact of the variants on EC coupling. Our results show that the polymorphisms are equally distributed among malignant hyperthermia negative, malignant hyperthermia equivocal, and malignant hyperthermia susceptible individuals. Interestingly, however, the presence of either one of these JP-45 variants decreased the sensitivity of the DHPR to activation. The presence of a JSRP1 variant may explain the variable phenotype seen in patients with malignant hyperthermia carrying the same mutation and, more importantly, may counteract the hypersensitivity of EC coupling caused by mutations in the RYR1 gene.

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