INTRACELLULAR CALCIUM-RELEASE CHANNELS - REGULATORS OF CELL LIFE AND DEATH

Intracellular Ca2+-release channels on the sarcoplasmic reticulum of s triated muscle [ryanodine receptors (RyRs)] and on the endoplasmic ret iculum of almost all types of cells [inositol 1,4,5-trisphosphate rece ptors (IP(3)Rs)] comprise a unique family of molecules that are struct urally and functionally distinct from all other known ion channels. Th ese channels play crucial roles in Ca2+-mediated signaling that trigge rs excitation-contraction coupling, T-lymphocyte activation, fertiliza tion, and many other cellular functions. Three forms of RyR have been identified: RyR1, expressed predominantly in skeletal muscle; RyR2, ex pressed predominantly in cardiac muscle; and RyR3, expressed in specia lized muscles and nonmuscle tissues including the brain. RyR channels are tetramers composed of four subunits each with a molecular mass of similar to 560,000 Da. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein known as the FK506 binding protein (FKBP). FKBP is the cytosolic receptor for the immunosuppressa nt drugs FK506 and rapamycin that inhibit the prolyl isomerase activit y of FKBP and can dissociate FKBP from RyRs. Rapamycin and FK506 incre ase the sensitivity of RyRs to agonists such as caffeine and could be a cause of cardiac dysfunction associated with high-dose immunosuppres sant therapy by promoting leakage of Ca2+ from the sarcoplasmic reticu lum. The role of prolyl isomerase activity of FKBP in regulating RyR f unction remains uncertain, and several models have been proposed that could explain how the channel is modulated by its association with FKB P. Three forms of IP(3)Rs (types 1, 2 and 3) have been characterized b y cDNA cloning. Most cells have at least one form of IP(3)R, and many express all three types. Like RyRs, the IP(3)R channels are tetramers composed of four subunits (similar to 300,000 Da each). IP(3)R1 functi on is regulated by at least two major cellular signaling pathways: the second messenger IP3 activates the channel, and phosphorylation by no nreceptor protein tyrosine kinases (e.g., Fyn) increase its open proba bility. During end-stage human heart failure, RyR2 mRNA and protein ar e downregulated, whereas IP(3)R1 is upregulated, suggesting that alter ed Ca2+-release channel levels may contribute to defects in Ca2+ homeo stasis. Cells that are deficient in IP(3)R1 exhibit defective T cell-r eceptor signaling and thus cannot be activated by T cell-receptor stim ulation. IP(3)R1-deficient cells are also resistant to induced apoptos is. Thus RyRs and IP(3)Rs play critical roles in fundamental and diver se signaling phenomena that include excitation-contraction coupling, T -cell activation, and programmed cell death.