CHARACTERIZATION OF A NOVEL CALCIUM STORE

细胞内钙库的动员由两种主要机制介导，即三磷酸肌醇（IP 3）途径和钙诱导的钙释放（CICR）机制。 我们的研究证实，Ca 2+商店也可以通过两个新的信使通过完全独立的途径动员。 环腺苷二磷酸核糖（cADPR）和烟酸腺嘌呤二核苷酸磷酸（NAADP）分别是NAD和NADP的新代谢产物。越来越多的证据表明cADPR是一种通过CICR发挥作用的通用Ca ~（2+）信使。 由NAADP介导的Ca 2+信号传导机制最近才被表征。 对NAADP敏感的钙库与对IP 3和cADPR敏感的钙库是可分离的。 NAADP激活的Ca 2+释放机制也完全独立于cADPR和IP 3激活的Ca 2+释放机制。然而，NAADP与cADPR相关，因为两者由相同的酶合成，但在不同的条件下。阐明这一迄今未知的NAADP介导的信号通路可能对我们理解信号转导机制产生重要影响。具体目标是：1。合成NAADP类似物。 2.建立内源性NAADP的检测方法。 3.研究NAADP敏感性钙库的亚细胞分布特征。 4.对NAADP敏感的Ca 2+库进行生化表征。5.确定NAADP敏感的Ca ~（2+）库在Ca ~（2+）波传播中的作用。

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.