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DPB162-AE, an inhibitor of store-operated Ca2+ entry, can deplete the endoplasmic reticulum Ca2+ store

Bittremieux, Mart, Gerasimenko, Julia V., Schuermans, Marleen, Luyten, Tomas, Stapleton, Eloise, Alzayady, Kamil J., De Smedt, Humbert, Yule, David I., Mikoshiba, Katsuhiko, Vangheluwe, Peter, Gerasimenko, Oleg V., Parys, Jan B. and Bultynck, Geert 2017. DPB162-AE, an inhibitor of store-operated Ca2+ entry, can deplete the endoplasmic reticulum Ca2+ store. Cell Calcium 62 10.1016/j.ceca.2017.01.015

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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 Orai1. 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0143-4160
Date of Acceptance: 27 January 2017
Last Modified: 11 Dec 2020 03:02

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