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Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high\u2010 and low\u2010frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic\u2010motility stages E18.5\u2013P3 showed that Ca<jats:sub>V<\/jats:sub>1.2\u2010positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2\u2010aminoethoxydiphenyl borate (2\u2010APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2\u2010APB resistant. We extended our results on L\u2010type channel\u2010dependent spontaneous activity and TTX\u2010resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro\u2010mechanical sensitivity in the enteric nervous system.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p><jats:p>What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity?<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>What is the main finding and its importance?<\/jats:bold><\/jats:p><jats:p>ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L\u2010type calcium channels and IP<jats:sub>3<\/jats:sub>R receptors, and the enteric nervous system exhibits a tetrodotoxin\u2010resistant mechanosensitive response.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p><jats:bold>Abstract figure legend<\/jats:bold> Tetrodotoxin\u2010resistant Ca<jats:sup>2+<\/jats:sup> rise induced by mechanical stimulation in the E18.5 mouse duodenum.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep091977","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T11:50:20Z","timestamp":1720525820000},"page":"1545-1556","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Tetrodotoxin\u2010resistant mechanosensitivity and L\u2010type calcium channel\u2010mediated spontaneous calcium activity in enteric neurons"],"prefix":"10.1113","volume":"109","author":[{"given":"Richard J.","family":"Amedzrovi Agbesi","sequence":"first","affiliation":[{"name":"Laboratoire Mati\u00e8re et Syst\u00e8mes Complexes UMR 7057 Universit\u00e9 Paris Cit\u00e9\/CNRS  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira","family":"El Merhie","sequence":"additional","affiliation":[{"name":"Laboratoire Mati\u00e8re et Syst\u00e8mes Complexes UMR 7057 Universit\u00e9 Paris Cit\u00e9\/CNRS  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick J.","family":"Spencer","sequence":"additional","affiliation":[{"name":"College of Medicine and Public Health Flinders University  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Hibberd","sequence":"additional","affiliation":[{"name":"College of Medicine and Public Health Flinders University  Adelaide South Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9713-1511","authenticated-orcid":false,"given":"Nicolas R.","family":"Chevalier","sequence":"additional","affiliation":[{"name":"Laboratoire Mati\u00e8re et Syst\u00e8mes Complexes UMR 7057 Universit\u00e9 Paris Cit\u00e9\/CNRS  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-005-0047-6"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-007-8001-0"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1899.sp000752"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2148"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.034"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1989.sp017762"},{"issue":"2","key":"e_1_2_9_8_1","first-page":"G422","article-title":"Analysis of the responses of myenteric neurons in the small intestine to chemical stimulation of the mucosa","volume":"273","author":"Bertrand P. 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