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• W1569016688 startingPage "1250" @default.
• W1569016688 abstract "Background Depletion of the Ca 2+ store by ryanodine receptor ( RyR ) agonists induces store‐operated Ca 2+ entry ( SOCE ). 4‐Chloro‐3‐ethylphenol (4‐ CEP ) and 4‐chloro‐ m ‐cresol (4‐ C m C ) are RyR agonists commonly used as research tools and diagnostic reagents for malignant hyperthermia. Here, we investigated the effects of 4‐ CEP and its analogues on SOCE . Experimental Approach SOCE and ORAI1 ‐3 currents were recorded by Ca 2+ imaging and whole‐cell patch recordings in rat L6 myoblasts and in HEK293 cells overexpressing STIM1 / ORAI1 ‐3. Key Results 4‐ CEP induced a significant release of Ca 2+ in rat L6 myoblasts, but inhibited SOCE . The inhibitory effect was concentration‐dependent and more potent than its analogues 4‐ C m C and 4‐chlorophenol (4‐ ClP ). In the HEK293 T‐REx cells overexpressing STIM1 / ORAI1 ‐3, 4‐ CEP inhibited the ORAI1 , ORAI2 and ORAI3 currents evoked by thapsigargin. The 2‐ APB ‐induced ORAI3 current was also blocked by 4‐ CEP . This inhibitory effect was reversible and independent of the Ca 2+ release. The two analogues, 4‐ C m C and 4‐ ClP , also inhibited the ORAI1 ‐3 channels. Excised patch and intracellular application of 4‐ CEP demonstrated that the action site was located extracellularly. Moreover, 4‐ CEP evoked STIM1 translocation and subplasmalemmal clustering through its Ca 2+ store‐depleting effect via the activation of RyR , but no effect on STIM1 redistribution was observed in cells co‐expressing STIM1 / ORAI1 ‐3. Conclusion and Implications 4‐ CEP not only acts as a RyR agonist to deplete the Ca 2+ store and trigger STIM1 subplasmalemmal translocation and clustering, but also directly inhibits ORAI1 ‐3 channels. These findings demonstrate a novel pharmacological property for the chlorophenol derivatives that act as RyR agonists." @default.
• W1569016688 created "2016-06-24" @default.
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• W1569016688 date "2014-02-27" @default.
• W1569016688 modified "2023-09-25" @default.
• W1569016688 title "The ryanodine receptor agonist 4-chloro-3-ethylphenol blocks ORAI store-operated channels" @default.
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• W1569016688 doi "https://doi.org/10.1111/bph.12528" @default.
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