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Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels.
Cell Calcium ( IF 4.3 ) Pub Date : 2020-08-29 , DOI: 10.1016/j.ceca.2020.102281
Xuexin Zhang 1 , Ping Xin 1 , Ryan E Yoast 1 , Scott M Emrich 1 , Martin T Johnson 1 , Trayambak Pathak 1 , J Cory Benson 1 , Iman Azimi 2 , Donald L Gill 1 , Gregory R Monteith 3 , Mohamed Trebak 4
Affiliation  

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+ (5μM), 2-APB (5 μM and 50 μM), 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.



中文翻译:

ORAI1、ORAI2 和 ORAI3 通道的不同药理学特征。

无处不在的 Ca 2+释放激活 Ca 2+(CRAC) 通道对许多生理功能至关重要。CRAC 功能的获得和丧失都与疾病有关。虽然 ORAI1 是 CRAC 通道的关键亚基,但最近的证据表明 ORAI2 和 ORAI3 与 ORAI1 异源化形成天然 CRAC 通道。此外,ORAI2 和 ORAI3 可以独立于 ORAI1 形成 CRAC 通道,表明不同的天然 CRAC 化学计量。然而,大多数可用的 CRAC 修饰剂被认为是针对 ORAI1,而对其对 ORAI2/3 或 ORAI 异聚体的影响知之甚少。在这里,我们使用 ORAI1/2/3 三空细胞来表达单个 ORAI1、ORAI2、ORAI3 或 ORAI1/2/3 串联体。我们发现 GSK-7975A 和 BTP2 基本上消除了 ORAI1 和 ORAI2 的活性,同时仅导致对 ORAI3 的部分抑制。有趣的是,Synta66 废除了 ORAI1 通道功能,同时增强 ORAI2 而对 ORAI3 没有影响。Synta66 抑制由串联 ORAI1-1、ORAI1-2 和 ORAI1-3 二聚体介导的 CRAC 通道活动,而 ORAI2-3 二聚体不受影响。CRAC 增强剂 IA65 显着增强了 ORAI1 和 ORAI1-1 的活性,对其他 ORAI 的影响很小。此外,我们表征了在 Gd 存在下单个 ORAI 同种型的特征3+ (5μM)、2-APB(5 μM 和 50 μM),以及细胞内和细胞外 pH 值的变化。我们的数据揭示了在 ORAI 无效背景中表达的 ORAI 同种型的独特药理学特征,并为广泛使用的 CRAC 药理学化合物的 ORAI 同种型选择性提供了新的见解。

更新日期:2020-09-05
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