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. 2025 Jun 25.
doi: 10.1113/JP288957. Online ahead of print.

Pancreatic acinar cell signalling and function exhibit an absolute requirement for activation of Gαq

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Pancreatic acinar cell signalling and function exhibit an absolute requirement for activation of Gαq

Takahiro Takano et al. J Physiol. .

Abstract

Elevated cytoplasmic [Ca2⁺] and protein kinase C (PKC) activation are key signalling events driving secretion in pancreatic acinar cells after stimulation by the secretagogues cholecystokinin (CCK) and acetylcholine (ACh). Although both ACh and CCK binding to their cognate receptors activates Gq/11 proteins, leading to inositol 1,4,5-trisphosphate (IP₃)-mediated Ca2⁺ release and diacylglycerol (DAG)-dependent PKC activation, it has been proposed that physiological CCK stimulation bypasses this canonical pathway, instead mobilizing Ca2⁺ via production of nicotinic acid adenine dinucleotide phosphate (NAADP). We reassessed the role of Gq/11 signalling in CCK-induced responses using a bioluminescence resonance energy transfer (BRET) assay, demonstrating that both CCK1 (CCK1R) and muscarinic M3 receptors (M3R) engage Gq/11 along with other Gα subunits. Importantly YM-254890, a Gq/11 antagonist, inhibited coupling through Gq/11 but did not alter the interactions of CCK1R or M3R with other G protein families. YM-254890 eliminated CCK1R- and M3R-induced Ca2⁺ signals in isolated acinar cells. Consistent with the in vitro data, systemic CCK injection, intrinsic neural stimulation or feeding failed to elicit Ca2⁺ responses in vivo in mice pre-treated with YM-254890, indicating that physiological stimulation of Ca2+ signalling events requires Gq/11 activation. Additionally YM-254890 suppressed Ca2⁺-activated Cl⁻ currents, a key event underlying fluid secretion, and amylase secretion in acini after CCK or ACh stimulation. These findings establish that CCK- and ACh-induced exocrine pancreatic secretion strictly requires Gq/11 activation, leading to IP₃ generation, DAG production and downstream signalling that is essential for physiological function. KEY POINTS: An increase in cytoplasmic Ca2+ and PKC activity after CCK and ACh stimulation following feeding is a pivotal event in the activation of fluid secretion and exocytosis from pancreatic acinar cells. In contrast to ACh, it has been suggested that at physiological concentrations, CCK stimulation results in the production of nicotinic acid dinucleotide adenine phosphate, without activating the canonical Gq/11 pathway, and the production of inositol 1,4,5,-trisphosphate (IP3) and diacylglycerol (DAG). After having established that YM-254890 is an exquisitely selective Gq/11 inhibitor, we show that Ca2+ signals stimulated in vitro and in vivo in response to both M3R and CCK1R stimulation are completely inhibited by YM-254890. YM-254890 completely abrogates Ca2+-activated Cl- current activation, pivotal for fluid secretion together with amylase secretion stimulated by both M3R and CCK1R activation. We conclude that ACh and CCK stimulation results in Gq/11 activation, an increase in IP3 and DAG, and this event is fundamentally important for exocrine function.

Keywords: Ca2+ signalling; Gαq/11; YM‐254890; diacylglycerol; exocytosis; inositol 1,4,5‐trisphosphate; nicotinic acid dinucleotide adenine phosphate; pancreatic acinar cells.

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