Ryanodine receptor defects in muscle genetic diseases
Ryanodine receptor defects in muscle genetic diseases
复制标题
DOI：
10.1016/j.bbrc.2004.08.029
复制
发表时间：
2004-10-01
影响因子：
3.1
通讯作者：
Brini, M
中科院分区：
文献类型：
--
作者：
Brini, M
Ryanodine receptor（RyR）是一种同源四聚体的钙离子释放通道，是产生钙信号的主要因素之一。三个基因编码RyRs的三种异构体，其具有组织限制性分布。RyR1和RyR2是典型的肌肉细胞，RyR1最初被认为是骨骼肌类型，RyR2是心脏类型。然而，RyR1和RyR2最近已在许多其它细胞类型中发现，包括例如外周B和T淋巴细胞。相反，RyR3广泛分布于细胞中。RyR1和RyR2位于肌浆网（SR）的一个专门部分，即末端池，它是SR Ca 2+储存的一部分，释放Ca 2+以控制肌肉收缩的过程。RyR3的具体作用尚未确定：可能，其与其他RyR亚型的共表达有助于定性调节肌细胞和神经元中的Ca 2+依赖性过程。编码RyR1和RyR2的基因中的几个突变已在骨骼肌和心肌的常染色体显性遗传疾病中被鉴定，例如恶性高热（MH）、中央核心病（CCD）、儿茶酚胺能多态性室性心动过速（CPVT）和致心律失常性右心室发育不良2型（ARVD 2）。最近，还描述了隐性遗传的CCD病例。MH是一种药物遗传性疾病，但其他表现为先天性肌病。即使它们的临床表型已经很好地建立，特别是在骨骼肌中，但产生这些疾病的分子机制尚不清楚。许多关于细胞模型的研究试图阐明与不同突变相关的分子缺陷，但是理解同一基因中的突变如何产生如此一系列不同的病理特征和严重程度差异很大的疾病的问题仍然是开放的。这篇综述将考虑RyR突变的分子和细胞效应，总结最近的数据在文献中的Ca2+失调，这可能会导致更好地了解RyR的功能。(C)2004年爱思唯尔公司All rights reserved.
Ryanodine receptor (RyR), a homotetrameric Ca2+ release channel, is one of the main actors in the generation of Ca2+ signals that trigger muscle contraction. Three genes encode three isoforms of RyRs, which have tissue-restricted distribution. RyR1 and RyR2 are typical of muscle cells, with RyR1 originally considered the skeletal muscle type and RyR2 the cardiac type. However, RyR1 and RyR2 have recently been found in numerous other cell types, including, for instance, peripheral B and T lymphocytes. In contrast, RyR3 is widely distributed among cells. RyR1 and RyR2 are localized in a specialized portion of the sarcoplasmic reticulum (SR), the terminal cisternae, which is the portion of the SR Ca2+ store that releases Ca2+ to control the process of muscle contraction. A specific role for RyR3 has not yet been established: probably, its co-expression with the other RyR isoforms contributes to qualitatively modulate Ca2+-dependent processes in muscle cells and in neurons. Several mutations in the genes encoding RyR1 and RyR2 have been identified in autosomal dominant diseases of skeletal and cardiac muscle, such as malignant hyperthermia (MH), central core disease (CCD), catecholaminergic polymorphic ventricular tachycardia (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2). More recently, CCD cases with recessive inheritance have also been described. MH is a pharmacogenetic disease, but the others manifest as congenital myopathies. Even if their clinical phenotypes are well established, particularly in skeletal muscle, the molecular mechanisms that generate the conditions are not clear. A number of studies on cellular models have attempted to elucidate the molecular defects associated with the different mutations, but the problem of understanding how mutations in the same gene generate such an array of diverse pathological traits and diseases of widely different degrees of severity is still open. This review will consider the molecular and cellular effects of RyR mutations, summarizing recent data in the literature on Ca2+ dysregulation, which may lead to a better understanding of the functioning of RyRs. (C) 2004 Elsevier Inc. All rights reserved.