Cyclic ADP-Ribose and NAADP in Vascular Regulation and Diseases

Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), two intracellular Ca²⁺ 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 Ca²⁺ release with a slow Ca²⁺-induced Ca²⁺ 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 Ca²⁺ 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.