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Alternative splicing gives rise to several TRPM3 variants. The functional consequences of these splice isoforms are poorly understood. Here, the pharmacological properties of TRPM3 variants arising from alternative splicing in the pore\u2010forming region were compared.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Calcium microfluorimetry and patch clamp recordings were used to compare the properties of heterologously expressed TRPM3\u03b11 (long pore variant) and TRPM3\u03b12\u2013\u03b16 (short pore variants). Furthermore, site\u2010directed mutagenesis was done to investigate the influence of the length of the pore loop on the channel function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>All short pore loop TRPM3\u03b1 variants (TRPM3\u03b12\u2013\u03b16) were activated by the neurosteroid pregnenolone sulphate (PS) and by nifedipine, whereas the long pore loop variant TRPM3\u03b11 was insensitive to either compound. In contrast, TRPM3\u03b11 was robustly activated by clotrimazole, a compound that does not directly activate the short pore variants but potentiates their responses to PS. Clotrimazole\u2010activated TRPM3\u03b11 currents were largely insensitive to established TRPM3\u03b12 antagonists and were only partially inhibited upon activation of the \u03bc opioid receptor. Finally, by creating a set of mutant channels with pore loops of intermediate length, we showed that the length of the pore loop dictates differential channel activation by PS and clotrimazole.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Alternative splicing in the pore\u2010forming region of TRPM3 defines the channel's pharmacological properties, which depend critically on the length of the pore\u2010forming loop.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.14\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.14\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15223","type":"journal-article","created":{"date-parts":[[2020,8,12]],"date-time":"2020-08-12T02:50:06Z","timestamp":1597200606000},"page":"3560-3575","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Pharmacological properties of TRPM3 isoforms are determined by the length of the pore loop"],"prefix":"10.1111","volume":"179","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1727-9517","authenticated-orcid":false,"given":"Katharina","family":"Held","sequence":"first","affiliation":[{"name":"Laboratory of Endometrium, Endometriosis and Reproductive Medicine, Department of Development and Regeneration KU Leuven  Leuven Belgium"},{"name":"Laboratory of Ion Channel Research VIB\u2013KU Leuven Center for Brain and Disease Research  Leuven Belgium"},{"name":"Department of Molecular Medicine KU Leuven  Leuven Belgium"},{"name":"DM Centre for Brain Health, Department of Medicine University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo Davide","family":"Aloi","sequence":"additional","affiliation":[{"name":"Laboratory of Endometrium, Endometriosis and Reproductive Medicine, Department of Development and Regeneration KU Leuven  Leuven Belgium"},{"name":"Laboratory of Ion Channel Research VIB\u2013KU Leuven Center for Brain and Disease Research  Leuven Belgium"},{"name":"Department of Molecular Medicine KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Cristina Nogueira","family":"Freitas","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research VIB\u2013KU Leuven Center for Brain and Disease Research  Leuven Belgium"},{"name":"Department of Molecular Medicine KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Janssens","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research VIB\u2013KU Leuven Center for Brain and Disease Research  Leuven Belgium"},{"name":"Department of Molecular Medicine KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Segal","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research VIB\u2013KU Leuven Center for Brain and Disease Research  Leuven Belgium"},{"name":"Department of Molecular Medicine KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Przibilla","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Pharmacology and Toxicology\/Center for Molecular Signaling (PZMS) Saarland University  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan Ernst","family":"Philipp","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Pharmacology and Toxicology\/Center for Molecular Signaling (PZMS) Saarland University  Homburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Tian","family":"Wang","sequence":"additional","affiliation":[{"name":"DM Centre for Brain Health, Department of Medicine University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-5821","authenticated-orcid":false,"given":"Thomas","family":"Voets","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research VIB\u2013KU Leuven Center for Brain and Disease Research  Leuven Belgium"},{"name":"Department of Molecular Medicine KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2502-0409","authenticated-orcid":false,"given":"Joris","family":"Vriens","sequence":"additional","affiliation":[{"name":"Laboratory of Endometrium, Endometriosis and Reproductive Medicine, Department of Development and Regeneration KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,8,28]]},"reference":[{"issue":"1","key":"e_1_2_11_2_1","first-page":"S142","article-title":"THE CONCISE GUIDE TO PHARMACOLOGY 2019\/20: Ion channels","volume":"176","author":"Alexander S. 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