Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) as Messengers for Calcium Mobilization

Abstract

Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate were discovered >2 decades ago. That they are second messengers for mobilizing Ca 2؉ stores has since been firmly established. Separate stores and distinct Ca 2؉ channels are targeted, with cyclic ADP-ribose acting on the ryanodine receptors in the endoplasmic reticulum, whereas nicotinic acid adenine dinucleotide phosphate mobilizes the endolysosomes via the two-pore channels. Despite the structural and functional differences, both messengers are synthesized by a ubiquitous enzyme, CD38, whose crystal structure and catalytic mechanism have now been well elucidated. How this novel signaling enzyme is regulated remains largely unknown and is the focus of this minireview.

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

“…In the case of noncompetitive inhibition, increasing the amount of substrate does not affect the level of inhibition. This difference may be important in considering the optimal inhibitor of CD38, since CD38 catalyzes reactions that lead to a wide range of second messengers, some of which are potent calcium (Ca 21 ) mobilizers (Lee, 2012;Gul et al, 2016). It remains possible that increased production of these second messengers contributes to ischemia-induced Ca 21 overload in myocytes (Zimmerman and Hülsmann, 1966;Hausenloy and Yellon, 2013).…”

Autocrine/Paracrine Function of Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) for Glucose Homeostasis in Pancreatic β-Cells and Adipocytes

“…NAADP induces Ca 2ϩ release through a mechanism distinct from those of other Ca 2ϩ -mobilizing messengers, such as inositol trisphosphate and cyclic ADP-ribose. The latter two messengers act on their respective receptors present on the endoplasmic reticulum, whereas NAADP targets acidic Ca 2ϩ stores (4,5). Interestingly, however, a family of enzymes called ADP-ribosyl cyclases catalyzes the formation of both cyclic ADP-ribose and NAADP via two distinct reactions and using two different substrates, respectively.…”

“…3 is the most potent Ca 2ϩ -releasing second messenger that has been shown to regulate many physiological processes, including insulin secretion from pancreatic ␤-cells (1)(2)(3)(4)(5). NAADP induces Ca 2ϩ release through a mechanism distinct from those of other Ca 2ϩ -mobilizing messengers, such as inositol trisphosphate and cyclic ADP-ribose.…”

Inseparable tandem: evolution chooses ATP and Ca2+to control life, death and cellular signalling

“…For intracellular Ca 2þ release, the cell possesses different types of Ca 2þ -release channels activated by distinct compounds represented by (i) inositol 1,4,5-trisphosphate (InsP 3 ) formed from phosphatidyl inositol 4,5-bisphosphate (PInsP 2 , a component of lipid membranes) and binding to InsP 3 -receptor-type Ca 2þ -release channels (InsP 3 R, [87]); (ii) by Ca 2þ ions themselves, which activate ryanodine-receptors (RyR) evolutionarily related to the InsP 3 -receptor at the protozoan level where intermediates of the two channel types are also found [26,38,39,88,89]; and (iii) by nicotinic acid adenosine dinucleotide phosphate (NAADP), which activates two-pore channels (TPCs) of acidic Ca 2þ stores [90]. In metazoans, RyRs are activated by Ca 2þ [91] and by cyclic adenosine diphosphoribose (cADPR) formed from the glycolytic H þ acceptor NAD [92]. Both NAD and nicotinamide adenine dinucleotide phosphate (NADP), but probably also PInsP 2 , have been available in early eukaryote evolution-at least the key components [93] and enzymes [94] are found in protozoa.…”