Li Pin-Lan, Zhang Yang, Abais Justine M, Ritter Joseph K, Zhang Fan
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, VA 23298, USA.
Messenger (Los Angel). 2013 Jun 1;2(2):63-85. doi: 10.1166/msr.2013.1022.
Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), two intracellular Ca mobilizing second messengers, have been recognized as a fundamental signaling mechanism regulating a variety of cell or organ functions in different biological systems. Here we reviewed the literature regarding these ADP-ribosylcyclase products in vascular cells with a major focus on their production, physiological roles, and related underlying mechanisms mediating their actions. In particular, several hot topics in this area of research are comprehensively discussed, which may help understand some of the controversial evidence provided by different studies. For example, some new models are emerging for the agonist receptor coupling of CD38 or ADP-ribosylcyclase and for the formation of an acidic microenvironment to facilitate the production of NAADP in vascular cells. We also summarized the evidence regarding the NAADP-mediated two-phase Ca release with a slow Ca-induced Ca release (CICR) and corresponding physiological relevance. The possibility of a permanent structural space between lysosomes and sarcoplasmic reticulum (SR), as well as the critical role of lysosome trafficking in phase 2 Ca release in response to some agonists are also explored. With respect to the molecular targets of NAADP within cells, several possible candidates including SR ryanodine receptors (RyRs), lysosomal transient receptor potential-mucolipin 1 (TRP-ML1) and two pore channels (TPCs) are presented with supporting and opposing evidence. Finally, the possible role of NAADP-mediated regulation of lysosome function in autophagy and atherogenesis is discussed, which may indicate a new direction for further studies on the pathological roles of cADPR and NAADP in the vascular system.
环磷酸腺苷核糖（cADPR）和烟酰胺腺嘌呤二核苷酸磷酸（NAADP）是两种可动员细胞内钙离子的第二信使，已被公认为是一种基本的信号传导机制，可调节不同生物系统中多种细胞或器官的功能。在此，我们回顾了有关这些ADP核糖环化酶产物在血管细胞中的文献，主要关注它们的产生、生理作用以及介导其作用的相关潜在机制。特别地，我们全面讨论了该研究领域的几个热点话题，这可能有助于理解不同研究提供的一些有争议的证据。例如，关于CD38或ADP核糖环化酶的激动剂受体偶联以及形成酸性微环境以促进血管细胞中NAADP产生的一些新模型正在出现。我们还总结了有关NAADP介导的两相钙释放以及缓慢的钙诱导钙释放（CICR）及其相应生理相关性的证据。还探讨了溶酶体与肌浆网（SR）之间存在永久结构空间的可能性，以及溶酶体运输在响应某些激动剂时在第二阶段钙释放中的关键作用。关于细胞内NAADP的分子靶点，提出了几种可能的候选者，包括SR兰尼碱受体（RyRs）、溶酶体瞬时受体电位黏脂蛋白1（TRP-ML1）和双孔通道（TPCs），并给出了支持和反对的证据。最后，讨论了NAADP介导的溶酶体功能调节在自噬和动脉粥样硬化中的可能作用，这可能为进一步研究cADPR和NAADP在血管系统中的病理作用指明新的方向。
