Study of the IP_3 receptor family and its diverse roles in various physiological functions

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In this study, we have analyzed the structural and functional diversity of the IP_3 receptor family.1.We have cloned human type 1,2, and 3 receptor cDNAs of the IP_3R family, and have studied their structures, IP_3-binding activities, expression in various tissues and cell-lines, and chromosomal loci.2.We have localized the IP_3-binding site, calmodulin binding site and two N-linked glycosylation sites on the mouse type 1 IP_3 receptor. We have proposed a membrane-spanning model and a channel pore region.3.We have studied the expression of the type 1 receptor in various cell systems ; the up-regulation during the differentiation of a HL-60 cell line toward a neutrophilic cell lineage, the down-regulation in an SH-SY5Y neuroblastoma chronically stimulated with carbacol, and the reduction in cerebella of human spinocerebellar degeneration patients (olivopontocerebellar atrophy [OPCA] and hereditary cerebellar atrophy of Holmes type).4.We have developed transgenic mice carrying the fusion gene composed of the type 1 receptor promoter and beta-galactosidase gene, by which dynamic expression of the type 1 receptor can be easily visualized by assaying beta-galactosidase activity with chromogenic substrates.5.We have studied the expression of other molecules involved in calcium increase in neuronal cells, i.e., ryanodine receptors and voltage-dependent calcium channels, and have suggested the presence of complex calcium signalling systems in the nervous system.