Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum
Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum
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DOI：
10.1016/j.bbamcr.2010.11.009
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发表时间：
2011-05-01
影响因子：
5.1
通讯作者：
Zvaritch, Elena
中科院分区：
文献类型：
--
作者：
MacLennan, David H.;Zvaritch, Elena
本文就肌浆网钙释放通道、兰尼定受体和钙离子结合蛋白的缺陷引起的肌肉紊乱和疾病作一综述。它提供了过去半个世纪关于恶性高热(MH)、中枢性核心病(CCD)和儿茶酚胺能多形性室性心动过速(CPVT)的研究亮点的时间线，这些研究导致兰诺定受体(RyR)、钙调素受体(CASQ)和二氢吡啶受体(CACNA1S)基因被确定为致病突变的位置。随后描述了致病突变对蛋白质功能影响的功能分析方法，重点研究了突变如何影响肌浆网自发的(储存超载诱导的)钙释放，这是MH和CPVT的根本原因。随后的章节描述了通过分析携带MH和CCD引起的突变的敲击小鼠株系获得的结果，包括Casq1基因敲除。综述最后介绍了两个机械论模型。第一部分展示了钙稳态失调如何导致同时涉及RyR和Casq蛋白的肌肉疾病。第二种是中枢核心形成理论，其中钙离子释放不均匀导致肌肉收缩不均匀，被认为是突变型异四聚体Ryanodine受体的特殊三级结构的内在属性，也是骨骼肌核心形成的根本原因。本文是一期特刊的一部分，题为：第11届欧洲钙研讨会。(C)2010年，爱思唯尔出版。
This review focuses on muscle disorders and diseases caused by defects in the Ca2+ release channels of the sarcoplasmic reticulum, the ryanodine receptors, and in the luminal, low affinity, high capacity Ca2+-binding proteins, calsequestrins. It provides a time line over the past half century of the highlights of research on malignant hyperthermia (MH), central core disease (CCD) and catecholaminergic polymorphic ventricular tachycardia (CPVT), that resulted in the identification of the ryanodine receptor (RYR), calsequestrin (CASQ) and dihydropyridine receptor (CACNA1S) genes as sites of disease-causing mutations. This is followed by a description of approaches to functional analysis of the effects of disease-causing mutations on protein function, focusing on studies of how mutations affect spontaneous (store overload-induced) Ca2+-release from the sarcoplasmic reticulum, the underlying cause of MH and CPVT. Subsequent sections describe results obtained by analysis of knockin mouse lines carrying MH- and CCD-causing mutations, including a Casq1 knockout. The review concludes with the presentation of two mechanistic models. The first shows how dysregulation of Ca2+ homeostasis can lead to muscle diseases involving both RyR and Casq proteins. The second describes a theory of central core formation wherein non-uniformity of Ca2+ release, resulting in non-uniformity of muscle contraction, is presented as an intrinsic property of the specific tertiary structure of mutant heterotetrameric ryanodine receptors and as the underlying cause of core formation in skeletal muscle. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. (C) 2010 Published by Elsevier B.V.