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The ryanodine receptor agonist 4-chloro-3-ethylphenol blocks ORAI store-operated channels.
Br J Pharmacol. 2014 Mar; 171(5):1250-9.BJ

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-CmC) 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-CmC 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-CmC 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.

Authors+Show Affiliations

Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, UK.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24670147

Citation

Zeng, Bo, et al. "The Ryanodine Receptor Agonist 4-chloro-3-ethylphenol Blocks ORAI Store-operated Channels." British Journal of Pharmacology, vol. 171, no. 5, 2014, pp. 1250-9.
Zeng B, Chen GL, Daskoulidou N, et al. The ryanodine receptor agonist 4-chloro-3-ethylphenol blocks ORAI store-operated channels. Br J Pharmacol. 2014;171(5):1250-9.
Zeng, B., Chen, G. L., Daskoulidou, N., & Xu, S. Z. (2014). The ryanodine receptor agonist 4-chloro-3-ethylphenol blocks ORAI store-operated channels. British Journal of Pharmacology, 171(5), 1250-9. https://doi.org/10.1111/bph.12528
Zeng B, et al. The Ryanodine Receptor Agonist 4-chloro-3-ethylphenol Blocks ORAI Store-operated Channels. Br J Pharmacol. 2014;171(5):1250-9. PubMed PMID: 24670147.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The ryanodine receptor agonist 4-chloro-3-ethylphenol blocks ORAI store-operated channels. AU - Zeng,Bo, AU - Chen,Gui-Lan, AU - Daskoulidou,Nikoleta, AU - Xu,Shang-Zhong, PY - 2013/07/05/received PY - 2013/10/21/revised PY - 2013/11/06/accepted PY - 2014/3/28/entrez PY - 2014/3/29/pubmed PY - 2014/10/29/medline KW - 4-chloro-3-ethylphenol KW - 4-chloro-m-cresol KW - ORAI KW - STIM1 KW - ryanodine receptors KW - store-operated Ca2+ channels SP - 1250 EP - 9 JF - British journal of pharmacology JO - Br J Pharmacol VL - 171 IS - 5 N2 - 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-CmC) 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-CmC 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-CmC 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/24670147/The_ryanodine_receptor_agonist_4_chloro_3_ethylphenol_blocks_ORAI_store_operated_channels_ L2 - https://doi.org/10.1111/bph.12528 DB - PRIME DP - Unbound Medicine ER -