{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T16:26:18Z","timestamp":1789230378888,"version":"build-2803163510"},"reference-count":92,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001316","name":"University of Kent","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001316","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust project","doi-asserted-by":"publisher","award":["GR074359"],"award-info":[{"award-number":["GR074359"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","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"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Store-operated Ca2+ entry (SOCE) is a key regulator of cytosolic Ca2+ (Ca2+cyt). Presynaptic SOCE can be activated by ligands like \u03b1-latrotoxin, which acts through the presynaptic G-protein-coupled receptor latrophilin-1 (LPHN1), inducing Ca2+ influx and neurotransmitter release. To understand how SOCE-associated proteins contribute to LPHN1 signaling in neurons, we used mouse neuroblastoma NB2a cells as a genetically tractable neuronal model. The cells were stably transfected with exogenous LPHN1 or its non-signaling mutant and stimulated with the non-pore-forming \u03b1-latrotoxin mutant LTXN4C, a known trigger of neurotransmitter release. LPHN1 expression increased the proportion of neuron-like cells and upregulated the voltage-gated Ca2+ channels Cav1.2 and Cav2.1. LPHN1 stimulation by LTXN4C induced a small Ca2+ release sensitive to thapsigargin, and a strong, gradual influx of Ca2+, which was insensitive to thapsigargin. Single-cell imaging revealed that this influx consisted of desynchronized high-amplitude Ca2+ oscillations in individual cells. This response was reduced by Orai2 knockdown and completely blocked by the Cav2.1\/2.2 inhibitor \u03c9-conotoxin MVIIC. We conclude that LPHN1 activation by LTXN4C primes Ca2+ stores and induces the opening of Cav2.1\/2.2 channels. These channels mediate an initial Ca2+ influx that triggers Ca2+-induced Ca2+ release and SOCE. This mechanism, elucidated in model cells, can explain how LTXN4C stimulates neurotransmitter release.<\/jats:p>","DOI":"10.3390\/ijms262211200","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T09:44:53Z","timestamp":1763631893000},"page":"11200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Mechanism of LTXN4C-Induced Ca2+ Influx Involves Latrophilin-Mediated Activation of Cav2.x Channels"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2171-6716","authenticated-orcid":false,"given":"Jennifer K.","family":"Blackburn","sequence":"first","affiliation":[{"name":"Medway School of Pharmacy, University of Kent, Chatham ME4 4TB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7239-8554","authenticated-orcid":false,"given":"John-Paul","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9814-9660","authenticated-orcid":false,"given":"Evelina","family":"Petitto","sequence":"additional","affiliation":[{"name":"Medway School of Pharmacy, University of Kent, Chatham ME4 4TB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8100-0365","authenticated-orcid":false,"given":"Dietmar","family":"Cholewa","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Inselspital Bern, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4466-2642","authenticated-orcid":false,"given":"Elizaveta","family":"Fasler-Kan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Inselspital Bern, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8208-1905","authenticated-orcid":false,"given":"Kirill E.","family":"Volynski","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Imperial College London, London SW7 2AZ, 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, Chatham ME4 4TB, UK"},{"name":"Department of Biological Sciences, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1113\/jphysiol.1967.sp008183","article-title":"The Timing of Calcium Action during Neuromuscular Transmission","volume":"189","author":"Katz","year":"1967","journal-title":"J. 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