Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells

Abstract

Many hormones and neurotransmitters evoke Ca2+ release from intracellular stores, often triggering agonist-specific signatures of intracellular Ca2+ concentration. Inositol trisphosphate (InsP3) and cyclic adenosine 5'-diphosphate-ribose (cADPR) are established Ca2+-mobilizing messengers that activate Ca2+ release through intracellular InsP3 and ryanodine receptors, respectively. However, in pancreatic acinar cells, neither messenger can explain the complex pattern of Ca2+ signals triggered by the secretory hormone cholecystokinin (CCK). We show here that the Ca2+-mobilizing molecule nicotinic acid adenine dinucleotide phosphate (NAADP), an endogenous metabolite of beta-NADP, triggers a Ca2+ response that varies from short-lasting Ca2+ spikes to a complex mixture of short-lasting (1-2s) and long-lasting (0.2-1 min) Ca2+ spikes. Cells were significantly more sensitive to NAADP than to either cADPR or InsP3, whereas higher concentrations of NAADP selectively inactivated CCK-evoked Ca2+ signals in pancreatic acinar cells, indicating that NAADP may function as an intracellular messenger in mammalian cells.

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

“…These data are consistent with the lack of effect of pH [20] and Ca# + [12] on NAADP-induced Ca# + release from sea urchin egg homogenates, and are in stark contrast to the reported effects of pH and Ca# + on the binding of cADPR [21] and IP $ [22]. The insensitivity of NAADP binding to Ca# + further indicates that NAADP receptors do not exhibit Ca# + -induced Ca# + release [12], and supports a role for NAADP in providing a ' trigger ' Ca# + release that is subsequently amplified by IP $ and\or cADPR receptors [16]. Preparations that were fully responsive to both IP $ and cADPR but not NAADP in Ca# + release assays (occasionally encountered ; 3 out of 120 preparations) did not bind [$#P]NAADP (Figure 3).…”

“…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.…”

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

“…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.…”

“…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).…”