Molecular properties of inositol 1,4,5-trisphosphate receptors

The receptors for the second messenger inositol 1,4,5-trisphosphate (IP₃) constitute a family of Ca²⁺ channels responsible for the mobilization of intracellular Ca²⁺ stores. Three different gene products (types I-III) have been isolated, encoding polypeptides which assemble as large tetrameric structures. Recent molecular studies have advanced our knowledge about the structure, regulation and function of IP₃ receptors. For example, several Ca²⁺- binding sites and a Ca²⁺-calmodulin-binding domain have been mapped within the type I IP₃ receptor, and studies on purified cerebellar IP₃ receptors propose a second Ca²⁺-independent calmodulin-binding domain. In addition, minimal requirements for the binding of immunophilins and the formation of tetramers have been identified. Overexpression of IP₃ receptors has provided further clues to the regulation of individual IP₃ receptor isoforms present within cells, and the role that they play in the generation of IP₃-dependent Ca²⁺ signals. Inhibition of IP₃ receptor function and expression, and analysis of mutant IP₃ receptors, suggests that IP₃ receptors are involved in such diverse cellular processes as proliferation and apoptosis and are thus, necessary for normal development. Our understanding of the complex spatial and temporal nature of cytosolic Ca²⁺ increases and the role that these Ca²⁺ signals play in cell function depend upon our knowledge of the structure and the regulation of IP₃ receptors. This review focuses on the molecular properties of these ubiquitous intracellular Ca²⁺ channels.