Biochemical and Biophysical Research Communications
Ryanodine receptor defects in muscle genetic diseases
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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