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This review outlines the rationale for targeting TRPC ion channels for drug development, with specific focus on TRPC4 and TRPC5. We provide preclinical evidence that the lack of TRPC4 and TRPC5 channels or its pharmacological inhibition attenuate fear and anxiety without impairing other behaviors in mice. We also report on clinical studies of BI 1358894, a small molecule inhibitor of TRPC4\/5 ion channels, demonstrating reduced psychological and physiological responses to induced anxiety\/panic-like symptoms in healthy volunteers. Furthermore, we highlight an imaging study that investigated the acute effects of BI 1358894 and showed reduced activation in several brain regions involved in emotional processing. We conclude that these findings demonstrate a critical role for TRPC4 and TRPC5 in emotional processing, even though it remains an open question if the biological signatures of TRPC4\/5 inhibition reported here translate into clinical efficacy and indicate that a TRPC4\/5 inhibitor might provide a more effective treatment of internalizing disorders.<\/jats:p>","DOI":"10.1007\/s00406-024-01890-0","type":"journal-article","created":{"date-parts":[[2024,9,29]],"date-time":"2024-09-29T16:15:25Z","timestamp":1727626525000},"page":"1599-1610","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["TRPC4\/5 inhibitors: Phase I results and proof of concept studies"],"prefix":"10.1007","volume":"275","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4229-6658","authenticated-orcid":false,"given":"Simone","family":"Grimm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Just","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene","family":"Fuertig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer B.","family":"Dwyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas M.","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Wunder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,29]]},"reference":[{"key":"1890_CR1","doi-asserted-by":"publisher","first-page":"100341","DOI":"10.1016\/j.lanepe.2022.100341","volume":"16","author":"G Castelpietra","year":"2022","unstructured":"Castelpietra G, Knudsen AKS, Agardh EE et al (2022) The burden of mental disorders, substance use disorders and self-harm among young people in Europe, 1990\u20132019: findings from the global burden of Disease Study 2019. 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