Role of Ryanodine Receptors

Abstract

Recent findings on the ryanodine receptor of vertebrates, a Ca-release channel protein for the caffeine- and ryanodine-sensitive Ca pools, are reviewed in this article. Three distinct genes, i.e., ryr1, ryr2, and ryr3, express different isoforms in specific locations: Ryr1 in skeletal muscle and Purkinje cells of cerebellum; Ryr2 in cardiac muscle and brain, especially cerebellum; Ryr3 in skeletal muscle of nonmammalian vertebrates, the corpus striatum, and limbic cortex of brain, smooth muscles, and the other cells in vertebrates. While only one isoform (Ryr1) is expressed in mammalian skeletal muscles, two isoforms (alpha- and beta-isoforms expressed by ryr1 and ryr3, respectively) are found in nonmammalian vertebrate skeletal muscles. Although the coexistence of two isoforms may merely be related to differentiation and specialization, the biological significance remains to be clarified. Ryanodine receptors in vertebrate skeletal muscles are believed to mediate two different modes of Ca release: Ca(2+)-induced Ca release and action potential-induced Ca release. All results obtained so far with any isoform of ryanodine receptor are related to Ca(2+)-induced Ca release and show very similar characteristics. Ca(2+)-induced Ca release, however, cannot be the underlying mechanism of Ca release on skeletal muscle activation. Susceptibility of the ryanodine receptor's ryanodine-binding activity to modification by physical factors, such as osmolality of the medium, might be related to action potential-induced Ca release. A hypothesis of molecular interaction in view of the plunger model of action potential-induced Ca release is discussed, suggesting that the model could be compatible with Ryr1 and Ryr3, but incompatible with Ryr2. The functional relevance of ryanodine receptor isoforms, especially Ryr3, in brain also remains to be clarified. Among ryr1 gene-related diseases, malignant hyperthermia was the first to be identified; however, there is still the possibility of involvement of the other genes. Central core disease has been added to the list recently. A molecular approach for the diagnosis and treatment of diseases is now in progress.

Calcium-Induced Calcium Release in Skeletal Muscle

“…The vast majority of the studies of RyR and CICR have been performed since then, and much information has been accumulated (see reviews in Refs. 11,33,66,70,78,167,169,170,198,244,248,257,281), although many problems remain unanswered.…”

Caffeine Stimulates Amyloid β‐Peptide Release from β‐Amyloid Precursor Protein‐Transfected HEK293 Cells

“…Calcium homeostasis may play a pivotal role in the neuronal degeneration that occurs in AD and other degenerative disorders (Greenamyre and Young, 1989;Siesjö et al, 1989;Weiss and Choi, 1991), as well as in various myopathic conditions (Wrogemann and Pena, 1976;Bodensteiner and Engel, 1978;Ogawa, 1994 (Yankner et al, 1990;Pike et al, 1991) may be mediated by reactive oxygen species, membrane damage, and impairment of ion-motive ATPases (Mark et al, 1995). The resulting loss of calcium homeostasis leads to a potentiation of, or vulnerability to, depolarization-and excitotoxic amino acid-induced calcium influx (Koh et al, 1990;Mattson et al, 1993).…”

“…Brain or type 3 RYRs are expressed in human hippocampus, cortex, and corpus striatum (Stein et al, 1992;Sorrentino and Volpe, 1993). Their mode of activation is likely to involve a calcium-induced calcium release (CICR) phenomenon (McPherson et al, 1991;Ogawa, 1994).Previously, we used human embryonic kidney 293 (HEK293) cells to show that general changes in cytosolic or luminal free calcium concentration ([Ca 2~I~) following application of ionophore influence Aß production. The ßAPP-transfected HEK293 cells used in our studies are a proven model for the chemistry of amyloid production in AD.…”

“…Brain or type 3 RYRs are expressed in human hippocampus, cortex, and corpus striatum (Stein et al, 1992;Sorrentino and Volpe, 1993). Their mode of activation is likely to involve a calcium-induced calcium release (CICR) phenomenon (McPherson et al, 1991;Ogawa, 1994).…”

Three‐dimensional architecture of the skeletal muscle ryanodine receptor

“…Ryanodine receptors (RyRs) are intracellular calcium release channels found in a variety of vertebrate tissues (for reviews see [1][2][3][4]). In mammals, three isoforms of the gene have been identified, one of which (RyR1), is expressed primarily in skeletal muscle [5,6].…”