Resolving the topological enigma in Ca2+-signaling by cyclic ADP-ribose and NAADP [Signal Transduction]

October 31st, 2019 by Hon Cheung Lee, Yong Juan Zhao

Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structurally distinct messengers that mobilize the endoplasmic and endo-lysosomal Ca2+-stores, respectively. Both are synthesized by CD38 molecule (CD38), which has long been thought to be a type II membrane protein whose catalytic domain, intriguingly, faces to the outside of the cell. Accordingly, for more than 20 years it has remained unresolved how CD38 can use cytosolic substrates such as NAD and NADP to produce messengers that target intracellular Ca2+-stores. The discovery of type III CD38 whose catalytic domain faces the cytosol has now begun to clarify this topological conundrum. This article reviews the ideas and clues leading to the discovery of the type III CD38; highlights an innovative approach for uncovering its natural existence, and discusses the regulators of its activity, folding and degradation. We also review the compartmentalization of cADPR and NAADP biogenesis. We further discuss the possible mechanisms that promote type III CD38 expression and appraise a proposal of a Ca2+-signaling mechanism based on substrate limitation and product translocation. The surprising finding of another enzyme that produces cADPR and NAADP, sterile alpha and TIR motif containing1 (SARM1), is described. SARM1 regulates axonal degeneration and has no sequence similarity with CD38, but can catalyze the same set of multi-reactions and has the same cytosolic orientation as the type III CD38. The intriguing finding that SARM1 is activated by nicotinamide mononucleotide to produce cADPR and NAADP suggests that it may function as a regulated Ca2+-signaling enzyme like CD38.