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It is involved in many pathological and physiological processes, making it a potential therapeutic target for various diseases, including Alzheimer's disease, Parkinson's disease, and cancers. New analytical techniques are beneficial for gaining a deeper understanding of its involvement in disease pathogenesis and for advancing the drug discovery for TRPM2\u2010related diseases. In this work, we present the application of collision\u2010induced affinity selection mass spectrometry (CIAS\u2010MS) for the direct identification of ligands binding to TRPM2. CIAS\u2010MS circumvents the need for high mass detection typically associated with mass spectrometry of large membrane proteins. Instead, it focuses on the detection of small molecules dissociated from the ligand\u2010protein\u2010detergent complexes. This affinity selection approach consolidates all affinity selection steps within the mass spectrometer, resulting in a streamlined process. We showed the direct identification of a known TRPM2 ligand dissociated from the protein\u2010ligand complex. We demonstrated that CIAS\u2010MS can identify binding ligands from complex mixtures of compounds and screened a compound library against TRPM2. We investigated the impact of voltage increments and ligand concentrations on the dissociation behavior of the binding ligand, revealing a dose\u2010dependent relationship.<\/jats:p>","DOI":"10.1002\/cbic.202300790","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T22:31:05Z","timestamp":1705703465000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identification of Ligands for Ion Channels: TRPM2"],"prefix":"10.1002","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7046-5270","authenticated-orcid":false,"given":"Yushu","family":"Gu","sequence":"first","affiliation":[{"name":"Griffith Institute for Drug Discovery Griffith University  46 Don Young Rd, Brisbane Queensland 4111 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0930-3617","authenticated-orcid":false,"given":"Miaomiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery Griffith University  46 Don Young Rd, Brisbane Queensland 4111 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-5158","authenticated-orcid":false,"given":"Linlin","family":"Ma","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery Griffith University  46 Don Young Rd, Brisbane Queensland 4111 Australia"},{"name":"School of Environment and Science Griffith University  N34 1.29, Nathan Campus, Brisbane Queensland 4111 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4022-2623","authenticated-orcid":false,"given":"Ronald J.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Griffith Institute for Drug Discovery Griffith University  46 Don Young Rd, Brisbane Queensland 4111 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"\u00a0"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.36409"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200810109"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2018.31"},{"key":"e_1_2_8_5_1","unstructured":"\u00a0"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0558-4"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302414"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19074"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1010678108"},{"key":"e_1_2_8_10_1","unstructured":"\u00a0"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0270-1"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03396.x"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4081-14.2015"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-022-02723-8"},{"key":"e_1_2_8_15_1","unstructured":"\u00a0"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2014.07.001"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-015-9769-7"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.118"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI76042"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27236"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1322657111"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.620922"},{"key":"e_1_2_8_23_2","first-page":"83","volume":"13","author":"Park Y. 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