DPB162-AE, an inhibitor of store-operated Ca2+ entry, can deplete the endoplasmic reticulum Ca2+ store
DPB162-AE, an inhibitor of store-operated Ca2+ entry, can deplete the endoplasmic reticulum Ca2+ store
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DOI：
10.1016/j.ceca.2017.01.015
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发表时间：
2017-03-01
期刊：
影响因子：
4
通讯作者：
Bultynck, Geert
中科院分区：
文献类型：
--
作者：
Bittremieux, Mart;Gerasimenko, Julia V.;Bultynck, Geert
钙池操纵的钙内流（SOCE）是非兴奋细胞中一条重要的钙信号通路，调节细胞的多种功能。为了研究其生理作用，使用药理学工具，如2-氨基乙基二苯基硼酸酯（2-APB）来影响SOCE。2-APB是最具特征的SOCE抑制剂之一。然而，2-APB在较低浓度下也激活SOCE，同时抑制肌醇1，4，5-三磷酸受体（IP 3R）、肌/内质网Ca 2 +-ATP酶（SERCA）和其他离子通道，如TRP通道。正因为如此，已经开发了与2-APB相比更有效和更选择性地抑制SOCE的2-APB类似物。最近开发的DPB 162-AE是2-APB的结构二苯基硼酸酯异构体，其通过阻断STIM 1和Drell之间的功能偶联来选择性地抑制SOCE电流。然而，我们观察到DPB 162-AE在完全SOCE抑制所需的浓度下对ER Ca 2+库含量的不利影响。DPB 162-AE通过减少细胞系以及原代细胞中的ER Ca 2+储存来增加细胞溶质Ca 2+水平。DPB 162-AE不影响SERCA活性，但引起Ca 2+从ER泄漏，即使在应用SERCA抑制剂毒胡萝卜素后。IP 3Rs部分地促进了DPB 162-AE诱导的Ca 2+渗漏，因为抑制和遗传抑制IP 3R功能降低了DPB 162-AE对ER储存含量的影响，但没有完全阻断。我们的研究结果表明，在某些条件下，SOCE抑制剂DPB 162-AE可以通过诱导足够的SOCE抑制所需浓度的Ca 2+泄漏途径来降低ER Ca 2+库含量。(C)2017爱思唯尔有限公司版权所有
Store-operated Ca2+ entry (SOCE), an important Ca2+ signaling pathway in non-excitable cells, regulates a variety of cellular functions. To study its physiological role, pharmacological tools, like 2-aminoethyl diphenylborinate (2-APB), are used to impact SOCE. 2-APB is one of the best characterized SOCE inhibitors. However, 2-APB also activates SOCE at lower concentrations, while it inhibits inositol 1,4,5-trisphosphate receptors (IP3Rs), sarco/endoplasmic reticulum Ca2+-ATPases (SERCAs) and other ion channels, like TRP channels. Because of this, 2-APB analogues that inhibit SOCE more potently and more selectively compared to 2-APB have been developed. The recently developed DPB162-AE is such a structural diphenylborinate isomer of 2-APB that selectively inhibits SOCE currents by blocking the functional coupling between STIM1 and Drell. However, we observed an adverse effect of DPB162-AE on the ER Ca2+-store content at concentrations required for complete SOCE inhibition. DPB162-AE increased the cytosolic Ca2+ levels by reducing the ER Ca2+ store in cell lines as well as in primary cells. DPB162-AE did not affect SERCA activity, but provoked a Ca2+ leak from the ER, even after application of the SERCA inhibitor thapsigargin. IP3Rs partly contributed to the DPB162-AE-induced Ca2+ leak, since pharmacologically and genetically inhibiting IP3R function reduced, but not completely blocked, the effects of DPB162-AE on the ER store content. Our results indicate that, in some conditions, the SOCE inhibitor DPB162-AE can reduce the ER Ca2+-store content by inducing a Ca2+-leak pathway at concentrations needed for adequate SOCE inhibition. (C) 2017 Elsevier Ltd. All rights reserved.