{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:35:53Z","timestamp":1790019353378,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,2,27]],"date-time":"2014-02-27T00:00:00Z","timestamp":1393459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/08\/071\/25473"],"award-info":[{"award-number":["PG\/08\/071\/25473"]}],"id":[{"id":"10.13039\/501100000274","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":[[2014,3]]},"abstract":"Background<\/jats:title>Depletion of the Ca<\/jats:roman>2+<\/jats:sup><\/jats:styled-content> store by ryanodine receptor (RyR<\/jats:styled-content>) agonists induces store\u2010operated Ca<\/jats:roman>2+<\/jats:sup><\/jats:styled-content> entry (SOCE<\/jats:styled-content>). 4\u2010Chloro\u20103\u2010ethylphenol (4\u2010CEP<\/jats:styled-content>) and 4\u2010chloro\u2010m<\/jats:italic>\u2010cresol (4\u2010Cm<\/jats:italic>C<\/jats:styled-content>) are RyR<\/jats:styled-content> agonists commonly used as research tools and diagnostic reagents for malignant hyperthermia. Here, we investigated the effects of 4\u2010CEP<\/jats:styled-content> and its analogues on SOCE<\/jats:styled-content>.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>SOCE<\/jats:styled-content> and ORAI1<\/jats:styled-content>\u20103 currents were recorded by Ca<\/jats:roman>2+<\/jats:sup><\/jats:styled-content> imaging and whole\u2010cell patch recordings in rat L6<\/jats:styled-content> myoblasts and in HEK293<\/jats:styled-content> cells overexpressing STIM1<\/jats:styled-content>\/ORAI1<\/jats:styled-content>\u20103.<\/jats:p><\/jats:sec>Key Results<\/jats:title>4\u2010CEP<\/jats:styled-content> induced a significant release of Ca<\/jats:roman>2+<\/jats:sup><\/jats:styled-content> in rat L6<\/jats:styled-content> myoblasts, but inhibited SOCE<\/jats:styled-content>. The inhibitory effect was concentration\u2010dependent and more potent than its analogues 4\u2010Cm<\/jats:italic>C<\/jats:styled-content> and 4\u2010chlorophenol (4\u2010ClP<\/jats:styled-content>). In the HEK293 T\u2010REx<\/jats:styled-content> cells overexpressing STIM1<\/jats:styled-content>\/ORAI1<\/jats:styled-content>\u20103, 4\u2010CEP<\/jats:styled-content> inhibited the ORAI1<\/jats:styled-content>, ORAI2<\/jats:styled-content> and ORAI3<\/jats:styled-content> currents evoked by thapsigargin. The 2\u2010APB<\/jats:styled-content>\u2010induced ORAI3<\/jats:styled-content> current was also blocked by 4\u2010CEP<\/jats:styled-content>. This inhibitory effect was reversible and independent of the Ca<\/jats:roman>2+<\/jats:sup><\/jats:styled-content> release. The two analogues, 4\u2010Cm<\/jats:italic>C<\/jats:styled-content> and 4\u2010ClP<\/jats:styled-content>, also inhibited the ORAI1<\/jats:styled-content>\u20103 channels. Excised patch and intracellular application of 4\u2010CEP<\/jats:styled-content> demonstrated that the action site was located extracellularly. Moreover, 4\u2010CEP<\/jats:styled-content> evoked STIM1<\/jats:styled-content> translocation and subplasmalemmal clustering through its Ca<\/jats:roman>2+<\/jats:sup><\/jats:styled-content> store\u2010depleting effect via the activation of RyR<\/jats:styled-content>, but no effect on STIM1<\/jats:styled-content> redistribution was observed in cells co\u2010expressing STIM1<\/jats:styled-content>\/ORAI1<\/jats:styled-content>\u20103.<\/jats:p><\/jats:sec>Conclusion and Implications<\/jats:title>4\u2010CEP<\/jats:styled-content> not only acts as a RyR<\/jats:styled-content> agonist to deplete the Ca<\/jats:roman>2+<\/jats:sup><\/jats:styled-content> store and trigger STIM1<\/jats:styled-content> subplasmalemmal translocation and clustering, but also directly inhibits ORAI1<\/jats:styled-content>\u20103 channels. These findings demonstrate a novel pharmacological property for the chlorophenol derivatives that act as RyR<\/jats:styled-content> agonists.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12528","type":"journal-article","created":{"date-parts":[[2013,11,26]],"date-time":"2013-11-26T05:21:51Z","timestamp":1385443311000},"page":"1250-1259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The ryanodine receptor agonist 4\u2010chloro\u20103\u2010ethylphenol blocks ORAI<\/scp> store\u2010operated channels"],"prefix":"10.1111","volume":"171","author":[{"given":"Bo","family":"Zeng","sequence":"first","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Research 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 Cardiovascular and Metabolic Research Hull York 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