The ryanodine receptor (RyR) is a protein essential for the excitation-contraction (E-C) coupling triggered by sarcoplasmic calcium release following T-tubular membrane depolarization in the skeletal muscle. Sera from patients with myasthenia gravis (MG), an autoimmune disease of neuromuscular transmission, contain not only anti-acetylcholine receptor (AChR) antibodies but also antibodies to various myofibrillary proteins. Among these, antibodies to RyR could explain the mechanism of contraction defect that accompanies to anti-AChR-induced transmission block, particularly in MG patients with thymoma. Expression of a specific segment of RyR (Asn-4997-Arg5017, the antibody that reacts with a 40 kDa protein in neoplastic thymus) was deserved in thymomas, and is suspected of sensitizing T-cells leading to the production of anti-RyR antibodies. A counterpart of this human disease is seen in spontaneous thymoma rat (Buffalo/Mna) as shown by the presence of anti-RyR-positive serum, impaired E-C coupling and anti-RyR peptide-stainable thymus cells. FK506, originally developed as an immunosuppressant, disrupts the tight association of FKBP-12 (one of the immunophilins) with RyR, resulting in an increased release of sarcoplasmic calcium and accelerated E-C coupling in muscle. This drug was given to MG patients and provided a pharmacologic benefit to contraction fatigue in addition to an immunologic effect, as supported by a study of RyR-implicated muscle contraction process. FK506 may also offer a potentially therapeutic effect on the RyR-related muscle dysfunction caused by a disturbance in neurotrophic influence.
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