Role of NAADP and cADPR in the Induction and Maintenance of Agonist-Evoked Ca2+ Spiking in Mouse Pancreatic Acinar Cells

Abstract

Nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic adenosine diphosphate ribose (cADPR) were first demonstrated to mobilize Ca2+ in sea urchin eggs. In the absence of direct measurements of these messengers, pharmacological studies alone have implicated these molecules as intracellular second messengers for specific cell surface receptor agonists. We now report that in mouse pancreatic acinar cells, cholecystokinin, but not acetylcholine, evokes rapid and transient increases in NAADP levels in a concentration-dependent manner. In contrast, both cholecystokinin and acetylcholine-mediated production of cADPR followed a very different time course. The rapid and transient production of NAADP evoked by cholecystokinin precedes the onset of the Ca2+ signal and is consistent with a role for NAADP in the initiation of the Ca2+ response. Continued agonist-evoked Ca2+ spiking is maintained by prolonged elevations of cADPR levels through sensitization of Ca2+ -induced Ca2+ -release channels. This study represents the first direct comparison of NAADP and cADPR measurements, and the profound differences observed in their time courses provide evidence in support of distinct roles of these Ca2+ -mobilizing messengers in shaping specific Ca2+ signals during agonist stimulation.

Second Messenger Function of Nicotinic Acid Adenine Dinucleotide Phosphate Revealed by an Improved Enzymatic Cycling Assay

“…2C), thus suggesting a role for NAADP during the generation of early, subcellular Ca 2ϩ signals upon TCR/CD3 stimulation as has already been proposed (26). A comparable rapid and transient elevation of NAADP levels has been reported for the stimulation of mouse pancreatic acinar cells with cholecystokinin (11). Also in these cells, a role for NAADP in the generation of small, localized Ca 2ϩ signals preceding global Ca 2ϩ -induced Ca 2ϩ release has been hypothesized (11).…”

“…This method takes advantage of the irreversible binding of NAADP to its yet uncharacterized receptor (46). With this assay, an NAADP concentration of 4 M has been determined in activated sea urchin sperms (13) as well as an increase in cellular NAADP levels upon stimulation of pancreatic beta cells with glucose (10), upon stimulation of murine pancreatic acinar cells with cholecystokinin (11), and upon stimulation of arterial smooth muscle cells with endothelin-1 (12). In addition, basal cellular concentrations of NAADP in erythrocytes (16 nM), rat hepatocytes (4.5 nM), and Escherichia coli cells (2.5 nM) have been reported (14).…”

“…Moreover because extracellular stimulation induces increases in intracellular NAADP levels, a second messenger function for NAADP has been proposed in a few experimental systems (for reviews, see Refs. 8 and 9), including murine pancreatic beta cells (10), murine pancreatic acinar cells (11), and arterial smooth muscle cells (12). However, the determination of NAADP is still difficult because the data published so far were obtained by a radioligand binding assay requiring sea urchin egg homogenates as well as 32 P-labeled NAADP (10 -14).…”

Generation of Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate by CD38 for Ca2+ Signaling in Interleukin-8-treated Lymphokine-activated Killer Cells

“…Further studies remain to clarify how NAADPinduced Ca 2ϩ release from acidic stores triggers TRPM2 channels for Ca 2ϩ influx. NAADP is known as an important second messenger in glucose-stimulated pancreatic ␤ cells (16), cholecystokinin-mediated Ca 2ϩ signaling in pancreatic acinar cells (17), and histamine-induced myometrial cells (48). Moreover, NAADP has been shown to be produced by CD38 via a base-exchange reaction (11).…”

Synergistic regulation of endogenous TRPM2 channels by adenine dinucleotides in primary human neutrophils

“…On the other hand, there is strong evidence that reactive oxygen species not only liberate ADPR from mitochondria [35], but also cause activation of the DNA repair pathway involving poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG) with possibly subsequent increases of local ADPR levels acting on TRPM2 [36]. Furthermore, cholecystokinin (CCK) receptor-stimulation has been reported to increase NAADP and cADPR concentrations ultimately altering cellular calcium signals [37]. While human neutrophils are responsive to CCK stimulation, the physiological effect seems rather immunosuppressive than stimulatory in nature [38].…”