Inositol trisphosphate receptors:: Ca2+-modulated intracellular Ca2+ channels

The three subtypes of inositol trisphosphate (InsP(3)) receptor expressed in mammalian cells are each capable of forming intracellular Ca2+ channels that are regulated by both InsP(3) and cytosolic Ca2+. The InsP(3) receptors of many, though perhaps not all, tissues are biphasically regulated by cytosolic Ca2+: a rapid stimulation of the receptors by modest increases in Ca2+ concentration is followed by a slower inhibition at higher Ca2+ concentrations. Despite the widespread occurrence of this form of regulation and the belief that it is an important element of the mechanisms responsible for the complex Ca2+ signals evoked by physiological stimuli, the underlying mechanisms are not understood. Both accessory proteins and Ca2+-binding sites on InsP(3) receptors themselves have been proposed to mediate the effects of cytosolic Ca2+ on InsP(3) receptor function, bur the evidence is equivocal. The effects of cytosolic Ca2+ on InsP(3) binding and channel opening, and the possible means whereby the effects are mediated are discussed in this review. (C) 1998 Elsevier Science B.V. All rights reserved.