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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. ORCID:, Schuermans, Marleen, Luyten, Tomas, Stapleton, Eloise, Alzayady, Kamil J., De Smedt, Humbert, Yule, David I., Mikoshiba, Katsuhiko, Vangheluwe, Peter, Gerasimenko, Oleg V. ORCID:, 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: 21 Oct 2022 07:13

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