Co-expression in vertebrate tissues and cell lines of multiple inositol 1,4,5-trisphosphate (InsP3) receptors with distinct affinities for InsP3.

Inositol 1,4,5-trisphosphate (InsP3) is a ubiquitous second messenger in eukaryotic cells that triggers Ca2+ release from intracellular stores. Three types of InsP3 receptors have been identified in mammals. The three receptor types are encoded by homologous genes and are structurally similar, suggesting two alternative hypotheses about the biological significance of multiple InsP3 receptors: (a) the different InsP3 receptors could have similar functions as InsP3-gated Ca2+ channels, and the presence of multiple genes could then serve as a mechanism to allow tissue-specific differential expression of receptors; or (b) the different receptors are co-expressed in cells but have distinct biological roles in these cells. To test these hypothesis, we have investigated the similarities and differences between the expression, alternative splicing, and ligand binding of different receptors. Our results demonstrate co-expression of different InsP3 receptors in almost all tissues and cell lines tested. Although all receptor types exhibit a similar specificity for inositol phosphates, the different receptors have different affinities for InsP3, with a relative order of affinities of type II > type I > type III. These findings suggest that the presence of multiple InsP3-sensitive Ca2+ pools with differential responsiveness to InsP3 may be a general property of all cells mediated by the presence of multiple types of InsP3 receptors.