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The inositol 1,4,5 trisphosphate (IP3 ) receptor (IP3 R) is a Ca 2+ release channel that responds to the second messenger IP3 . Exquisite modulation of intracellular Ca 2+ release via IP3 Rs is achieved by the ability of IP3 R to integrate signals from numerous small molecules and proteins including nucleotides, kinases, and phosphatases, as well as nonenzyme proteins. Because the ion conduction pore composes only ∼5% of the IP3 R, the great bulk of this large protein contains recognition sites for these substances. Through these regulatory mechanisms, IP3 R modulates diverse cellular functions, which include, but are not limited to, contraction/ excitation, secretion, gene expression, and cellular growth. We review the unique properties of the IP3 R that facilitate cell-type and stimulus-dependent control of function, with special emphasis on protein-binding partners. [ABSTRACT FROM AUTHOR]

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ channels that exist as homo- or heterotetramers. In order to determine whether the N-terminal ligand-binding domain is in close physical proximity to the C-terminal pore domain, we prepared microsomal membranes from COS-7 cells expressing recombinant type I and type III IP3R isoforms. Trypsin digestion followed by cross-linking and co-immunoprecipitation of peptide fragments suggested an inter-subunit N- and C-terminal interaction in both homo- and heteratetramers. This observation was further supported by the ability of in vitro translated C-terminal peptides to interact specifically with an N-terminal fusion protein. Using a 45Ca2+ flux assay, we provide functional evidence that the ligand-binding domain of one subunit can gate the pore domain of an adjacent subunit. We conclude that common structural motifs are shared between the type I and type III IP3Rs and propose that the gating mechanism of IP3R Ca2+ channels involves the association of the N-terminus of one subunit with the C-terminus of an adjacent subunit in both homo- and heterotetrameric complexes. [ABSTRACT FROM AUTHOR]