{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:26:15Z","timestamp":1789230375564,"version":"build-2803163510"},"reference-count":113,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Kent core fund"},{"id":[{"id":"https:\/\/ror.org\/00xkeyj56","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["GR074359"],"award-info":[{"award-number":["GR074359"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"award":["GR074359"],"award-info":[{"award-number":["GR074359"]}],"id":[{"id":"https:\/\/ror.org\/029chgv08","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Science Research Council","doi-asserted-by":"publisher","award":["28\/B14085"],"award-info":[{"award-number":["28\/B14085"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Science Research Council","doi-asserted-by":"publisher","award":["BB\/D523078\/1"],"award-info":[{"award-number":["BB\/D523078\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"award":["28\/B14085"],"award-info":[{"award-number":["28\/B14085"]}],"id":[{"id":"https:\/\/ror.org\/00cwqg982","id-type":"ROR","asserted-by":"publisher"}]},{"award":["BB\/D523078\/1"],"award-info":[{"award-number":["BB\/D523078\/1"]}],"id":[{"id":"https:\/\/ror.org\/00cwqg982","id-type":"ROR","asserted-by":"publisher"}]},{"name":"University of Kent PhD studentships"},{"id":[{"id":"https:\/\/ror.org\/00xkeyj56","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Latrophilin 1 (LPHN1\/ADGRL1), an adhesion G-protein-coupled receptor (GPCR), is the principal receptor for \u03b1-latrotoxin (\u03b1LTX), a toxin that triggers massive neurotransmitter release. However, its endogenous signaling mechanism remains elusive. Here, we dissect the LPHN1 signaling pathway at the vertebrate neuromuscular junction, using the pore-deficient \u03b1LTX mutant LTXN4C as a selective agonist. Combining electrophysiological recordings from LPHN1 knockout mice with pharmacological inhibitors, calcium imaging, and biochemical assays, we delineate the cascade from receptor activation to spontaneous quantal acetylcholine release. We demonstrate that LPHN1 is specifically localized to the presynaptic membrane and mediates LTXN4C-evoked release. Upon activation, LPHN1 engages the G\u03b1q\u2013phospholipase C pathway to generate inositol 1,4,5-trisphosphate (IP3), triggering Ca2+ release from intracellular stores via IP3 receptors. This store depletion activates store-operated Ca2+ entry (SOCE), providing sustained Ca2+ required for LTXN4C-induced burst-like exocytosis. We uncover distinct roles for CaV2.1 and CaV1 channels in initiating and sustaining this response. These findings establish LPHN1 as a GPCR that harnesses intracellular stores and SOCE to drive spontaneous neurotransmission, revealing a novel signaling paradigm for adhesion GPCRs in presynaptic function.<\/jats:p>","DOI":"10.3390\/cells15090821","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T13:32:21Z","timestamp":1777555941000},"page":"821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Latrophilin-1-Mediated G\u03b1q Signaling, Store-Operated Ca2+ Entry, and CaV2.1 Activation Control Spontaneous Exocytosis at the Mouse Neuromuscular Junction"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9814-9660","authenticated-orcid":false,"given":"Evelina","family":"Petitto","sequence":"first","affiliation":[{"name":"Medway School of Pharmacy, University of Kent and Greenwich, Central Avenue, Chatham Maritime ME4 4TB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6400-1107","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric A.","family":"Meunier","sequence":"additional","affiliation":[{"name":"Division of Cell and Molecular Biology, Imperial College London, Exhibition Road, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8987-6196","authenticated-orcid":false,"given":"Sara","family":"Fidalgo","sequence":"additional","affiliation":[{"name":"Division of Cell and Molecular Biology, Imperial College London, Exhibition Road, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Colasante","sequence":"additional","affiliation":[{"name":"Unit\u00e9 d\u2019Embryologie Mol\u00e9culaire, Institut Pasteur, Unit\u00e9s de Recherche Associ\u00e9es 2578, Centre National de la Recherche Scientifique, 25 Rue du Dr Roux, 75724 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2171-6716","authenticated-orcid":false,"given":"Jennifer K.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Medway School of Pharmacy, University of Kent and Greenwich, Central Avenue, Chatham Maritime ME4 4TB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2670-6995","authenticated-orcid":false,"given":"Richard R.","family":"Ribchester","sequence":"additional","affiliation":[{"name":"Biomedical Sciences, University of Edinburgh, George Square, Edinburgh EH8 9JZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5712-8297","authenticated-orcid":false,"given":"Yuri A.","family":"Ushkaryov","sequence":"additional","affiliation":[{"name":"Medway School of Pharmacy, University of Kent and Greenwich, Central Avenue, Chatham Maritime ME4 4TB, UK"},{"name":"Division of Cell and Molecular Biology, Imperial College London, Exhibition Road, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1124\/pr.114.009647","article-title":"International Union of Basic and Clinical Pharmacology. 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