{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T05:29:30Z","timestamp":1768454970335,"version":"3.49.0"},"reference-count":46,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Foundation Flanders FWO","award":["G.0D1417N"],"award-info":[{"award-number":["G.0D1417N"]}]},{"name":"Research Foundation Flanders - FWO","award":["G.084515N"],"award-info":[{"award-number":["G.084515N"]}]},{"name":"Research Foundation-Flanders FWO","award":["G.0A6719N"],"award-info":[{"award-number":["G.0A6719N"]}]},{"name":"Research Council of the KU Leuven","award":["C14\/18\/106"],"award-info":[{"award-number":["C14\/18\/106"]}]},{"name":"Research Council of the KU Leuven","award":["C3\/21\/049"],"award-info":[{"award-number":["C3\/21\/049"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sex hormone steroidal drugs were reported to have modulating actions on the ion channel TRPM3. Pregnenolone sulphate (PS) presents the most potent known endogenous chemical agonist of TRPM3 and affects several gating modes of the channel. These includes a synergistic action of PS and high temperatures on channel opening and the PS-induced opening of a noncanonical pore in the presence of other TRPM3 modulators. Moreover, human TRPM3 variants associated with neurodevelopmental disease exhibit an increased sensitivity for PS. However, other steroidal sex hormones were reported to influence TRPM3 functions with activating or inhibiting capacity. Here, we aimed to answer how DHEAS, estradiol, progesterone and testosterone act on the various modes of TRPM3 function in the wild-type channel and two-channel variants associated with human disease. By means of calcium imaging and whole-cell patch clamp experiments, we revealed that all four drugs are weak TRPM3 agonists that share a common steroidal interaction site. Furthermore, they exhibit increased activity on TRPM3 at physiological temperatures and in channels that carry disease-associated mutations. Finally, all steroids are able to open the noncanonical pore in wild-type and DHEAS also in mutant TRPM3. Collectively, our data provide new valuable insights in TRPM3 gating, structure-function relationships and ligand sensitivity.<\/jats:p>","DOI":"10.3390\/ijms222413652","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"13652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Partial Agonistic Actions of Sex Hormone Steroids on TRPM3 Function"],"prefix":"10.3390","volume":"22","author":[{"given":"Eleonora","family":"Persoons","sequence":"first","affiliation":[{"name":"Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 Box 611, 3000 Leuven, Belgium"},{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, VIB Center for Brain & Disease Research, Herestraat 49 Box 802, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Kerselaers","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, VIB Center for Brain & Disease Research, Herestraat 49 Box 802, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Voets","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, VIB Center for Brain & Disease Research, Herestraat 49 Box 802, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2502-0409","authenticated-orcid":false,"given":"Joris","family":"Vriens","sequence":"additional","affiliation":[{"name":"Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 Box 611, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1727-9517","authenticated-orcid":false,"given":"Katharina","family":"Held","sequence":"additional","affiliation":[{"name":"Laboratory of Endometrium, Endometriosis & Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Herestraat 49 Box 611, 3000 Leuven, Belgium"},{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, VIB Center for Brain & Disease Research, Herestraat 49 Box 802, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1016\/j.jmb.2016.06.020","article-title":"Progesterone Receptor Signaling Mechanisms","volume":"428","author":"Grimm","year":"2016","journal-title":"J. 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