Moleculan mechanism of IP_3 receptor Ca^<2+> channel and the role of the receptor in signal transduction and growth and development

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Inositol 1,4,5-trisphosphate (InsP_3) is a second messenger which induces calcium release from the intracellular store sites. This InsP_3-induced calcium release (IICR) is mediated by an intracellular calcium release channel, InsP_3 receptor (InsP_3R). We have cloned the cDNAs of three different types of InsP_3R (types 1,2and3) so far, and have also found various alternatively-spliced variants of type 1 (neuronal type). The basic structure of all InsP_3R types is composed of three functional domains ; the ligand-binding domain (N-terminal portion) ; the modulatory domain (middle portion) which contains various sites for modulator-binding (ATP,calmodulin, Ca^<2+>, etc.) and phosphorylation (PKA,PKC,CaMKII) ; the channel domain (C-terminal portion) which contains six membrane-spanning segments and one putative "pore" -forming segment as the ion channel superfamily including voltage-sensitive and nucleotide-gated channels. InsP_3R forms a tetramer complex, so that each InsP_3-gated ion channel can have four ligand-binding sites. Our data indicate that each member of the InsP_3R family is differentially expressed in various cell-types, and in some cell-types can form heteromeric InsP_3R channels by assembling with the other receptor types. These results suggest that intracellular calcium signaling mediated by IICR in each cell-type is differently regulated. Thus, we recently have characterized the IICR activity of sole InsP_3R type by using the type-specifically purified receptor reconstituted in liposomes. We found that phosphorylation of type 1 receptor enhances IICR activity. We have also characterized the function role of the type 1 InsP_3R in some cell signalings by using the specific antibody as a channel blocker for the type 1 InsP_3R-mediated IICR.Calcium waves and oscillations in hamster eggs were clearly blocked. Introduction of the antisense nucleotide of the cDNA of Xenopus IP_3R which we cloned, into Xenopus eggs suppressed the egg activation.