CHARACTERIZATION OF A NOVEL CALCIUM STORE

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Mobilization of intracellular Ca2+ stores is mediated by two major mechanisms, the inositol trisphosphate (IP3)-pathway and the Ca2+-induced Ca2+ release (CICR) mechanism. Our research establishes that Ca2+ stores can also be mobilized by two new messengers via totally independent pathways. Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are novel metabolites of NAD and NADP, respectively. Accumulating evidence indicates cADPR is a general Ca2+ messenger acting via the CICR. The Ca2+ signaling mechanism mediated by NAADP has only recently been characterized. The Ca2+ stores that are sensitive to NAADP are separable from those sensitive to IP3 and cADPR. The Ca2+ release mechanism activated by NAADP is also completely independent of those activated by cADPR and IP3. Nevertheless, NAADP is related to cADPR since both are synthesized by the same enzymes but under different conditions. Elucidation of this hitherto unknown signaling pathway mediated by NAADP is likely to have an important impact on our understanding of signal transduction mechanisms. Specific aims are: 1. To synthesize analogs of NAADP. 2. To develop assays for endogenous NAADP. 3. To characterize the subcellular distribution of the NAADP-sensitive Ca2+ stores. 4. To characterize the NAADP-sensitive Ca2+ stores biochemically. 5. To determine the role of the NAADP-sensitive Ca2+ stores in propagation of Ca2+ waves.