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Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels


Zhang, X and Xin, P and Yoast, RE and Emrich, SM and Johnson, MT and Pathak, T and Benson, JC and Azimi, I and Gill, DL and Monteith, GR and Trebak, M, Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels, Cell Calcium, 91 Article 102281. ISSN 0143-4160 (2020) [Refereed Article]

Copyright Statement

Copyright 2020 Elsevier Ltd. All rights reserved.

DOI: doi:10.1016/j.ceca.2020.102281


The ubiquitous Ca2+ release-activated Ca2+ (CRAC) channel is crucial to many physiological functions. Both gain and loss of CRAC function is linked to disease. While ORAI1 is a crucial subunit of CRAC channels, recent evidence suggests that ORAI2 and ORAI3 heteromerize with ORAI1 to form native CRAC channels. Furthermore, ORAI2 and ORAI3 can form CRAC channels independently of ORAI1, suggesting diverse native CRAC stoichiometries. Yet, most available CRAC modifiers are presumed to target ORAI1 with little knowledge of their effects on ORAI2/3 or heteromers of ORAIs. Here, we used ORAI1/2/3 triple-null cells to express individual ORAI1, ORAI2, ORAI3 or ORAI1/2/3 concatemers. We reveal that GSK-7975A and BTP2 essentially abrogate ORAI1 and ORAI2 activity while causing only a partial inhibition of ORAI3. Interestingly, Synta66 abrogated ORAI1 channel function, while potentiating ORAI2 with no effect on ORAI3. CRAC channel activities mediated by concatenated ORAI1-1, ORAI1-2 and ORAI1-3 dimers were inhibited by Synta66, while ORAI2-3 dimers were unaffected. The CRAC enhancer IA65 significantly potentiated ORAI1 and ORAI1-1 activity with marginal effects on other ORAIs. Further, we characterized the profiles of individual ORAI isoforms in the presence of Gd3+ (5然), 2-APB (5然 and 50然), as well as changes in intracellular and extracellular pH. Our data reveal unique pharmacological features of ORAI isoforms expressed in an ORAI-null background and provide new insights into ORAI isoform selectivity of widely used CRAC pharmacological compounds.

Item Details

Item Type:Refereed Article
Keywords:pharmacological modulation, calcium, ORAI channels, calcium signaling, CRAC channels, ORAI1/2/3, pharmacological compounds, pH
Research Division:Biomedical and Clinical Sciences
Research Group:Pharmacology and pharmaceutical sciences
Research Field:Basic pharmacology
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in the biological sciences
UTAS Author:Azimi, I (Dr Iman Azimi)
ID Code:140761
Year Published:2020
Web of Science® Times Cited:41
Deposited By:Pharmacy
Deposited On:2020-09-03
Last Modified:2021-05-19

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