{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:28:02Z","timestamp":1790422082166,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T00:00:00Z","timestamp":1566172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["115974"],"award-info":[{"award-number":["115974"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81600381"],"award-info":[{"award-number":["81600381"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Mibefradil, a T\u2010type Ca<jats:sup>2+<\/jats:sup> channel blocker, has been investigated for treating solid tumours. However, its underlying mechanisms are still unclear. Here, we have investigated the pharmacological actions of mibefradil on Orai store\u2010operated Ca<jats:sup>2+<\/jats:sup> channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Human Orai1\u20103 cDNAs in tetracycline\u2010regulated pcDNA4\/TO vectors were transfected into HEK293 T\u2010REx cells with stromal interaction molecule 1 (STIM1) stable expression. The Orai currents were recorded by whole\u2010cell and excised\u2010membrane patch clamp. Ca<jats:sup>2+<\/jats:sup> influx or release was measured by Fura\u2010PE3\/AM. Cell growth and death were monitored by WST\u20101, LDH assays and flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Mibefradil inhibited Orai1, Orai2, and Orai3 currents dose\u2010dependently. The IC<jats:sub>50<\/jats:sub> for Orai1, Orai2, and Orai3 channels was 52.6, 14.1, and 3.8\u00a0\u03bcM respectively. Outside\u2010out patch demonstrated that perfusion of 10\u2010\u03bcM mibefradil to the extracellular surface completely blocked Orai3 currents and single channel activity evoked by 2\u2010APB. Intracellular application of mibefradil did not alter Orai3 channel activity. Mibefradil at higher concentrations (&gt;50\u00a0\u03bcM) inhibited Ca<jats:sup>2+<\/jats:sup> release but had no effect on cytosolic STIM1 translocation evoked by thapsigargin. Inhibition on Orai channels by mibefradil was structure\u2010related, as other T\u2010type Ca<jats:sup>2+<\/jats:sup> channel blockers with different structures, such as ethosuximide and ML218, had no or minimal effects on Orai channels. Moreover, mibefradil inhibited cell proliferation, induced apoptosis, and arrested cell cycle progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Mibefradil is a potent cell surface blocker of Orai channels, demonstrating a new pharmacological action of this compound in regulating cell growth and death, which could be relevant to its anti\u2010cancer activity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14788","type":"journal-article","created":{"date-parts":[[2019,7,4]],"date-time":"2019-07-04T18:39:28Z","timestamp":1562265568000},"page":"3845-3856","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Mibefradil, a T\u2010type Ca<sup>2+<\/sup> channel blocker also blocks Orai channels by action at the extracellular surface"],"prefix":"10.1111","volume":"176","author":[{"given":"Pengyun","family":"Li","sequence":"first","affiliation":[{"name":"Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School University of Hull  Hull UK"},{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education, and Institute of Cardiovascular Research Southwest Medical University  Luzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1489-5576","authenticated-orcid":false,"given":"Hussein N.","family":"Rubaiy","sequence":"additional","affiliation":[{"name":"Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School University of Hull  Hull UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui\u2010Lan","family":"Chen","sequence":"additional","affiliation":[{"name":"Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School University of Hull  Hull UK"},{"name":"Key Laboratory of Medical Electrophysiology, Ministry of Education, and Institute of Cardiovascular Research Southwest Medical University  Luzhou 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University of Hull  Hull UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7295-9347","authenticated-orcid":false,"given":"Shang\u2010Zhong","family":"Xu","sequence":"additional","affiliation":[{"name":"Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School University of Hull  Hull UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,8,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000338496.95579.56"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13884"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-174516"},{"key":"e_1_2_11_5_1","first-page":"540","article-title":"Voltage\u2010dependent blockade of diverse types of voltage\u2010gated Ca2+ channels expressed in Xenopus oocytes by the Ca2+ channel antagonist mibefradil (Ro 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