Two different but converging messenger pathways to intracellular Ca2+ release: the roles of nicotinic acid adenine dinucleotide phosphate, cyclic ADP-ribose and inositol trisphosphate

Abstract

Hormones and neurotransmitters mobilize Ca 2+ from the endoplasmic reticulum via inositol trisphosphate (IP 3 ) receptors, but how a single target cell encodes different extracellular signals to generate speci®c cyto-solic Ca 2+ responses is unknown. In pancreatic acinar cells, acetylcholine evokes local Ca 2+ spiking in the apical granular pole, whereas cholecystokinin elicits a mixture of local and global cytosolic Ca 2+ signals. We show that IP 3 , cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) evoke cytosolic Ca 2+ spiking by activating common oscillator units composed of IP 3 and ryanodine receptors. Acetylcholine activation of these common oscillator units is triggered via IP 3 receptors, whereas cholecystokinin responses are triggered via a different but converging pathway with NAADP and cyclic ADP-ribose receptors. Cholecystokinin potentiates the response to acetylcholine, making it global rather than local, an effect mediated speci®cally by cyclic ADPribose receptors. In the apical pole there is a common early activation site for Ca 2+ release, indicating that the three types of Ca 2+ release channels are clustered together and that the appropriate receptors are selected at the earliest step of signal generation.

Interactions between intracellular Ca2+ stores: Ca2+ released from the NAADP pool potentiates cADPR-induced Ca2+ release

“…The present study is the first to demonstrate a direct effect of the Ca 2+ released by NAADP on the apparent affinity of the ryanodine receptor for cADPR (Figure 4). This further indicates that NAADP may have an important role in the complex mechanism of intracellular Ca 2+ mobilization in several vertebrate and invertebrate cells (4,5,(16)(17)(18)20,21). In fact, the Ca 2+ released from the NAADP pool can modulate the intracellular Ca 2+ release by at least two different mechanisms: a) by priming the intracellular Ca 2+ pools (16) and b) by direct sensitization of the Ca 2+ -induced Ca 2+ release.…”

“…In contrast, the NAADP-induced Ca 2+ release does not behave like a Ca 2+ -induced Ca 2+ release (6,15). It has been proposed that the Ca 2+ released by NAADP could modulate the Ca 2+ -induced Ca 2+ release system activated by cADPR (18,20,21). However, no direct evidence for this action has been reported to date.…”

“…However, it has been proposed that in pancreatic acinar cells NAADP could be the trigger of Ca 2+ oscillations induced by cholecystokinin (20,21). The cited investigators proposed that Ca 2+ released by NAADP in response to cholecystokinin may activate the Ca 2+ -induced Ca 2+ release mediated by cADPR, leading to amplification of the Ca 2+ signaling and generation of the Ca 2+ oscillation (20,21). A similar role for NAADP has been proposed for the mobilization of Ca 2+ in starfish oocytes (18).…”

“…In fact, when normalized for the increase in extravesicular Ca 2+ upon the potentiation of the cADPR-induced Ca 2+ release, the effects of NAADP and of addition of Ca 2+ itself were near identical ( Figure 5). These data indicate that Ca 2+ released from the NAADP A B Multiple intracellular Ca 2+ stores are present in many cells (1,(4)(5)(6)20,21) and may play a role in several physiological processes including muscle contraction, exocrine and endocrine secretion, fertilization, neuronal activation and immune cell function (1,2,9,13,(16)(17)(18)20). Exactly how Ca 2+ exerts its intracellular effects is not completely understood.…”

Unique kinetics of nicotinic acid–adenine dinucleotide phosphate (NAADP) binding enhance the sensitivity of NAADP receptors for their ligand

“…1 To whom correspondence should be addressed (e-mail sandip.patel!pharmacology.oxford.ac.uk). Although the effects of NAADP have been most extensively characterized in sea urchin eggs, recent studies have extended the actions of NAADP to ascidian [14] and starfish [15] oocytes, mouse pancreatic acinar cells [16,17], rat brain microsomes [18], and plant preparations [19]. These studies strongly support a general role for NAADP-mediated Ca# + signalling.…”