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Despite the significant roles of TRPV2 in immunological response, cancer progression and cardiac development, pharmacological probes of TRPV2 remain to be identified. We aimed to discover TRPV2 inhibitors and to elucidate their molecular mechanism of action.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      Fluorescence\u2010based Ca\n                      <jats:sup>2+<\/jats:sup>\n                      assay in HEK\u2010293 cells expressing murine TRPV2 was used to identify plumbagin as a novel TRPV2 inhibitor. Patch\u2010clamp,\n                      <jats:italic>in silico<\/jats:italic>\n                      docking and site\u2010directed mutagenesis were applied to investigate the molecular mechanisms critical for plumbagin interaction. ELISA and qPCR were used to assess nitric oxide release and mRNA levels of inflammatory mediators, respectively. si\u2010RNA interference was used to knock down TRPV2 expression, which was validated by western blotting. Neurological and histological analyses were used to examine brain injury of mice following middle cerebral artery occlusion\/reperfusion (MCAO\/R).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Plumbagin is a potent TRPV2 negative allosteric modulator with an IC\n                      <jats:sub>50<\/jats:sub>\n                      value of 0.85\u2009\u03bcM, exhibiting &gt;14\u2010fold selectivity over TRPV1, TRPV3 and TRPV4. Plumbagin suppresses TRPV2 activity by decreasing the channel open probability without affecting the unitary conductance. Moreover, plumbagin binds to an extracellular pocket formed by the pore helix and flexible loop between transmembrane helices S5 and S6 of TRPV2. Plumbagin effectively suppresses LPS\u2010induced inflammation of BV\u20102 microglia and ameliorates brain injury of MCAO\/R mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Plumbagin is a novel pharmacological probe to study TRPV2 pathophysiology. TRPV2 is a novel molecular target for the treatment of neuroinflammation and ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.17343","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T00:15:43Z","timestamp":1728000943000},"page":"87-103","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Plumbagin, a novel TRPV2 inhibitor, ameliorates microglia activation and brain injury in a middle cerebral artery occlusion\/reperfusion mouse model"],"prefix":"10.1111","volume":"182","author":[{"given":"Meihuizi","family":"Ding","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy China Pharmaceutical University  Nanjing 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