Brooksbank R L, Badenhorst M E, Isaacs H, Savage N
Department of Physiology, University of the Witwatersrand Medical School, Parktown, Johannesburg, South Africa.
Anesthesiology. 1998 Sep;89(3):693-8. doi: 10.1097/00000542-199809000-00020.
FKBP12 is a protein that is closely associated with the ryanodine receptor type 1 of skeletal muscle and modulates Ca2+ release by the channel. The immunosuppressants FK506 and rapamycin both bind to FKBP12 and in turn dissociate the protein from the ryanodine receptor. By treating healthy human skeletal muscle strips with FK506 or rapamycin and then subjecting the strips to the caffeine-halothane contracture test, this study determined that FK506 and rapamycin alter the sensitivity of the muscle strip to halothane, caffeine, or both.
Skeletal muscle strips from 10 healthy persons were incubated in Krebs medium equilibrated with a 95% oxygen and 5% carbon dioxide mixture, which contained either 12 microM FK506 (n = 8) or 12 microM rapamycin (n = 6), for 15 min at 37 degrees C. The strips were subjected to the caffeine-halothane contracture test for malignant hyperthermia according to the European Malignant Hyperthermia Group protocol.
Treatment of normal skeletal muscle strips with FK506 and rapamycin resulted in halothane-induced contractures of 0.44+/-0.16 g and 0.6+/-0.49 g, respectively, at 2% halothane.
The results obtained show that pre-exposure of healthy skeletal muscle strips to either FK506 or rapamycin is sufficient to give rise to halothane-induced contractures. This is most likely caused by destabilization of Ca2+ release by the ryanodine receptor as a result of the dissociation of FKBP12. This finding suggests that a mutation in FKBP12 or changes in its capacity to bind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia.
FKBP12是一种与骨骼肌1型兰尼碱受体密切相关的蛋白质，可调节该通道的Ca2+释放。免疫抑制剂FK506和雷帕霉素均与FKBP12结合，进而使该蛋白与兰尼碱受体解离。通过用FK506或雷帕霉素处理健康人骨骼肌条，然后对这些条进行咖啡因-氟烷挛缩试验，本研究确定FK506和雷帕霉素会改变肌肉条对氟烷、咖啡因或两者的敏感性。
将10名健康人的骨骼肌条在含有95%氧气和5%二氧化碳混合物平衡的Krebs培养基中孵育，该培养基含有12微摩尔FK506（n = 8）或12微摩尔雷帕霉素（n = 6），在37℃下孵育15分钟。根据欧洲恶性高热组方案，对这些条进行用于恶性高热的咖啡因-氟烷挛缩试验。
用FK506和雷帕霉素处理正常骨骼肌条后，在2%氟烷浓度下，氟烷诱导的挛缩分别为0.44±0.16克和0.6±0.49克。
所得结果表明，将健康骨骼肌条预先暴露于FK506或雷帕霉素足以引起氟烷诱导的挛缩。这很可能是由于FKBP12解离导致兰尼碱受体释放Ca2+不稳定所致。这一发现表明，FKBP12的突变或其与兰尼碱受体结合能力的改变可能会改变骨骼肌兰尼碱受体对氟烷的敏感性，从而使个体易患恶性高热。
