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It is also incorporated in coronary stent coatings to prevent restenosis and in topical preparations for the treatment of skin disorders. Rapamycin\u2019s in vivo activities are generally ascribed to its binding to the protein FKBP12, leading to potent inhibition of the mechanistic target of rapamycin kinase (mTOR) by the FKBP12-rapamycin complex. The specific rapamycin-induced interaction between domains from mTOR and FKBP12 is also frequently employed in cell biological research, for rapid chemically-induced protein dimerization strategies. Here, we show that rapamycin activates TRPM8, a cation channel expressed in sensory nerve endings that serves as the primary cold sensor in mammals. Using a combination of electrophysiology, Saturation Transfer Triple-Difference (STTD) NMR spectroscopy, and molecular docking-based targeted mutagenesis, we demonstrate that rapamycin directly binds to human TRPM8. We identify a rapamycin-binding site in the groove between voltage sensor-like domain and the pore domain, distinct from the interaction sites of cooling agents and known TRPM8 agonists menthol and icilin. Related macrolide immunosuppressants act as partial TRPM8 agonists, competing with rapamycin for the same binding site. These findings identify a novel molecular target for rapamycin and provide new insights into the mechanisms of TRPM8 activation, which may assist in the development of therapies targeting this ion channel. Moreover, our findings also indicate that caution is needed when using molecular approaches based on rapamycin-induced dimerization to study ion channel regulation.\n                  <\/jats:p>","DOI":"10.7554\/elife.97341","type":"journal-article","created":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T09:25:41Z","timestamp":1715246741000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.97341","source":"Crossref","is-referenced-by-count":0,"title":["Direct modulation of TRPM8 ion channels by rapamycin and analog macrolide immunosuppressants"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4103-4333","authenticated-orcid":true,"given":"Bal\u00e1zs Istv\u00e1n","family":"T\u00f3th","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02xf66n48","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Cellular and Molecular Physiology, Department of Physiology, Faculty of Medicine, University of 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