Regulation of IP ₃ Receptors by IP ₃ and Ca ²⁺

Abstract

Inositol 1,4,5-trisphosphate ( IP ₃) receptors are intracellular Ca ²⁺ channels that mediate release of Ca ²⁺ from intracellular stores. The channels are oligomeric assemblies of four subunits, each of which has an N-terminal IP ₃-binding domain and each of which contributes to formation of the Ca ²⁺ channel. In mammals, three different genes encode IP ₃ receptors subunits and the type 1 receptor (and perhaps the type 2 receptor) is also expressed as splice variants. Further diversity arises from assembly of the receptor in hetero- and homo-tetrameric channels. The subtypes differ in their expression and regulation, but they share the key property of being regulated by both IP3 and cytosolic Ca ²⁺. All three mammalian IP ₃ subtypes, and probably also the IP ₃ receptors expressed in invertebrates, are biphasically regulated by cytosolic Ca2+, although the underlying mechanisms appear to differ between subtypes. The interactions between IP ₃ and Ca ²⁺ in controlling IP ₃ receptor gating, and the physiological significance of such regulation will be reviewed.