{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:29:11Z","timestamp":1790393351025,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Elevated cytoplasmic [Ca<jats:sup>2<\/jats:sup>\u207a] 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 G<jats:sub>q\/11<\/jats:sub> proteins, leading to inositol 1,4,5\u2010trisphosphate (IP\u2083)\u2010mediated Ca<jats:sup>2<\/jats:sup>\u207a release and diacylglycerol (DAG)\u2010dependent PKC activation, it has been proposed that physiological CCK stimulation bypasses this canonical pathway, instead mobilizing Ca<jats:sup>2<\/jats:sup>\u207a via production of nicotinic acid adenine dinucleotide phosphate (NAADP). We reassessed the role of G<jats:sub>q\/11<\/jats:sub> signalling in CCK\u2010induced responses using a bioluminescence resonance energy transfer (BRET) assay, demonstrating that both CCK1 (CCK1R) and muscarinic M3 receptors (M3R) engage G<jats:sub>q\/11<\/jats:sub> along with other G\u03b1 subunits. Importantly YM\u2010254890, a G<jats:sub>q\/11<\/jats:sub> antagonist, inhibited coupling through G<jats:sub>q\/11<\/jats:sub> but did not alter the interactions of CCK1R or M3R with other G protein families. YM\u2010254890 eliminated CCK1R\u2010 and M3R\u2010induced Ca<jats:sup>2<\/jats:sup>\u207a signals in isolated acinar cells. Consistent with the <jats:italic>in vitro<\/jats:italic> data, systemic CCK injection, intrinsic neural stimulation or feeding failed to elicit Ca<jats:sup>2<\/jats:sup>\u207a responses <jats:italic>in vivo<\/jats:italic> in mice pre\u2010treated with YM\u2010254890, indicating that physiological stimulation of Ca<jats:sup>2+<\/jats:sup> signalling events requires G<jats:sub>q\/11<\/jats:sub> activation. Additionally YM\u2010254890 suppressed Ca<jats:sup>2<\/jats:sup>\u207a\u2010activated Cl\u207b currents, a key event underlying fluid secretion, and amylase secretion in acini after CCK or ACh stimulation. These findings establish that CCK\u2010 and ACh\u2010induced exocrine pancreatic secretion strictly requires G<jats:sub>q\/11<\/jats:sub> activation, leading to IP\u2083 generation, DAG production and downstream signalling that is essential for physiological function.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16834-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>An increase in cytoplasmic Ca<jats:sup>2+<\/jats:sup> 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.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>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 G<jats:sub>q\/11<\/jats:sub> pathway, and the production of inositol 1,4,5,\u2010trisphosphate (IP<jats:sub>3<\/jats:sub>) and diacylglycerol (DAG).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>After having established that YM\u2010254890 is an exquisitely selective G<jats:sub>q\/11<\/jats:sub> inhibitor, we show that Ca<jats:sup>2+<\/jats:sup> signals stimulated <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> in response to both M3R and CCK1R stimulation are completely inhibited by YM\u2010254890.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>YM\u2010254890 completely abrogates Ca<jats:sup>2+<\/jats:sup>\u2010activated Cl<jats:sup>\u2212<\/jats:sup> current activation, pivotal for fluid secretion together with amylase secretion stimulated by both M3R and CCK1R activation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conclude that ACh and CCK stimulation results in Gq\/11 activation, an increase in IP<jats:sub>3<\/jats:sub> and DAG, and this event is fundamentally important for exocrine function.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp288957","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T00:50:26Z","timestamp":1750899026000},"page":"4497-4514","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Pancreatic acinar cell signalling and function exhibit an absolute requirement for activation of G\u03b1<sub>q<\/sub>"],"prefix":"10.1113","volume":"603","author":[{"given":"Takahiro","family":"Takano","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Franchini","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Larry E.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3807-3240","authenticated-orcid":false,"given":"Michelle","family":"Cooley","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy E.","family":"Groblewski","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Wisconsin  Madison Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-9350","authenticated-orcid":false,"given":"Cesare","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6743-0668","authenticated-orcid":false,"given":"David I.","family":"Yule","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,25]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.123.000722"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aad6281"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2209267119"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08030"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.63.1.99"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.11.2549"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.5.909"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201904844"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9OB00459A"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)43656-8"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00035.2006"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1114110"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2015.05.005"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.013453"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004278200"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abe3800"},{"key":"e_1_2_5_18_1","doi-asserted-by":"crossref","unstructured":"Huang K. T. Wagner L. E. Takano T. Lin X. X. Bagavant H. Deshmukh U. &Yule D. I.(2024).Dysregulated Ca(2+) signaling fluid secretion and mitochondrial function in a mouse model of early Sjogren's syndrome.bioRxiv.https:\/\/doi.org\/10.7554\/eLife.97069","DOI":"10.7554\/eLife.97069.1"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.4.2079"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.62.1.493"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.113.6.851"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.25.15765"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1995.269.3.G319"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)39317-2"},{"key":"e_1_2_5_25_1","first-page":"E652","article-title":"G protein in stimulation of PI hydrolysis by CCK in isolated rat pancreatic acinar cells","volume":"255","author":"Matozaki T.","year":"1988","journal-title":"American Journal of Physiology"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)63759-7"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006676-199201000-00010"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2006.07.070"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00143.2013"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1990.tb08162.x"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.181353798"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1992.sp019028"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pan.2022.12.010"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1987.67.3.1054"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1985.248.5.C535"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(85)91800-5"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00358-0"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1042\/bst0310950"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)85959-8"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00087.2004"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1998.274.4.G734"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2690483"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10156"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105203200"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/306067a0"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.66170"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.4380"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP284469"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP285461"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI169428"},{"issue":"12","key":"e_1_2_5_51_1","first-page":"1790","article-title":"Recommended tool compounds: application of YM\u2010254890 and FR900359 to interrogate galpha(q\/11)\u2010mediated signaling pathways","volume":"6","author":"Voss J. H.","year":"2023","journal-title":"American Chemical Society Pharmacology & Translational Science"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP285104"},{"key":"e_1_2_5_53_1","first-page":"167","volume-title":"The pancreas: Biology, pathobiology, and disease","author":"Williams J. A.","year":"1993"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.63.1.77"},{"key":"e_1_2_5_55_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1978.235.5.E517"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M311088200"},{"key":"e_1_2_5_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.04.033"},{"key":"e_1_2_5_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113628"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1999.276.1.G271"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.14.9093"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4160(91)90016-8"},{"key":"e_1_2_5_62_1","first-page":"G999","article-title":"A cloned CCK\u2010A receptor transduces multiple signals in response to full and partial agonists","volume":"265","author":"Yule D. I.","year":"1993","journal-title":"American Journal of Physiology"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP288957","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T13:13:10Z","timestamp":1759324390000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP288957"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,25]]},"references-count":61,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1113\/JP288957"],"URL":"https:\/\/doi.org\/10.1113\/jp288957","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,25]]},"assertion":[{"value":"2025-03-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}