ROLE OF RYANODINE RECEPTORS

Recent findings on the ryanodine receptor of vertebrates, a Ca-release channel protein for the caffeine- and ryanodine-sensitive Ca pools, a re reviewed in this article. Three distinct genes, i.e., ryr1, ryr2, a nd ryr3, express different isoforms in specific locations: Ryr1 in ske letal muscle and Purkinje cells of cerebellum; Ryr2 in cardiac muscle and brain, especially cerebellum; Ryr3 in skeletal muscle of nonmammal ian vertebrates, the corpus striatum, and limbic cortex of brain, smoo th muscles, and the other cells in vertebrates. While only one isoform (Ryr1) is expressed in mammalian skeletal muscles, two isoforms (alph a- and beta-isoforms expressed by ryr1 and ryr3, respectively) are fou nd in nonmammalian vertebrate skeletal muscles. Although the coexisten ce of two isoforms may merely be related to differentiation and specia lization, the biological significance remains to be clarified. Ryanodi ne receptors in vertebrate skeletal muscles are believed to mediate tw o different modes of Ca release: Ca2+-induced Ca release and action po tential-induced Ca release. All results obtained so far with any isofo rm of ryanodine receptor are related to Ca2+-induced Ca release and sh ow very similar characteristics. Ca2+-induced Ca release, however, can not be the underlying mechanism of Ca release on skeletal muscle activ ation. Susceptibility of the ryanodine receptor's ryanodine-binding ac tivity to modification by physical factors, such as osmolality of the medium, might be related to action potential-induced Ca release. A hyp othesis of molecular interaction in view of the plunger model of actio n potential-induced Ca release is discussed, suggesting that the model could be compatible with Ryr1 and Ryr3, but incompatible with Ryr2. T he functional relevance of ryanodine receptor isoforms, especially Ryr 3, in brain also remains to be clarified. Among ryr1 gene-related dise ases, malignant hyperthermia was the first to be identified; however, there is still the possibility of involvement of the other genes. Cent ral core disease has been added to the list recently. A molecular appr oach for the diagnosis and treatment of diseases is now in progress.