CHARACTERIZATION OF A NOVEL CALCIUM STORE

新型钙存储的特征

• 批准号: 6387191
• 负责人: HONCHEUNG LEE
• 金额: $ 25.54万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6387191
• 关键词: NAD(H) analog; NAD(H) phosphate; biological signal transduction; calcium; calcium flux; inositol phosphates; nucleic acid chemical synthesis

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.

细胞内Ca2+存储的动员是由两种主要机制介导的，即三磷酸肌醇（IP3） - 路径和Ca2+诱导的Ca2+释放（CICR）机制。 我们的研究表明，CA2+商店也可以通过完全独立的途径动员。 环状ADP-核糖（CADPR）和烟酸腺苷二核苷酸磷酸（NAADP）分别是NAD和NADP的新代谢产物。积累的证据表明CADPR是通过CICR作用的一般CA2+ Messenger。 NAADP介导的Ca2+信号传导机制直到最近才被表征。 对NAADP敏感的Ca2+商店与对IP3和CADPR敏感的商店可分开。 由NAADP激活的Ca2+释放机制也完全独立于CADPR和IP3激活的机制。然而，NAADP与CADPR有关，因为两者都是由相同的酶合成的，但在不同的条件下。 NAADP介导的迄今未知信号通路的阐明可能对我们对信号转导机制的理解产生重要影响。具体目的是：1。合成NAADP的类似物。 2。开发内源性NAADP的测定法。 3。表征NAADP敏感Ca2+存储的亚细胞分布。 4。以生化为代表NAADP敏感的Ca2+存储。 5。确定NAADP敏感的Ca2+存储在Ca2+波的传播中的作用。