Ryanodine receptor defects in muscle genetic diseases

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Abstract

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.

Section snippets

RyR structure and topology

The primary structures of the three ryanodine receptors (RyRs) have been elucidated by cDNA cloning. RyR genes are over 15,000 bp long and code for proteins of about 5000 amino acids. Mammalian RyR1, 2, and 3 proteins show a high degree of overall homology (about 70% of identity) with regions that are particularly conserved, and others where more variability is tolerated. The latter regions are thought to be responsible for the specific isoform characteristics and have been shown to be the

RyR mutations and associated defects

Given the essential role of the RyRs and their spatial organization in specialized portions of the sarcoplasmic reticulum, it is not surprising that dysfunctions in their operations may generate muscle or cardiac diseases. A number of mutations linked to diseases have been described in the RyR1 and in the RyR2 genes, and they will be discussed in detail in the next two sections. No mutations associated with inherited disease have so far been described for RyR3: phenotypes of knockout mice for

Conclusions

One of the questions still open in the field of Ca2+ signalling is the rationale for the existence of the large number of isoforms of the Ca2+-transporting proteins. InsP3 receptors and RyR receptors are co-expressed in neurons and in other cell types, including smooth muscle cells. This suggests that within one cell the combination of two or more types of channels, or of isoforms of the channels, may be necessary to satisfy different Ca2+ release demands. The existence of pathologies

Acknowledgments

The experimental work in the author’s laboratory was supported by Telethon (Grant GP0193Y01), the Italian University and Health Ministries, and the National Research Council of Italy (CNR, Agency 2000).

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