DPB162-AE, an inhibitor of store-operated Ca 2+ entry, can deplete the endoplasmic reticulum Ca 2+ store

Store-operated Ca entry (SOCE), an important Ca 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 SOC...

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Published in:Cell calcium (Edinburgh) 2017-03, Vol.62, p.60
Main Authors: 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, Bultynck, Geert
Format: Article
Language:English
Subjects:
Acinar Cells - drug effects
Acinar Cells - metabolism
Animals
Boron Compounds - pharmacology
Calcium - metabolism
Calcium Signaling - drug effects
Endoplasmic Reticulum - drug effects
Endoplasmic Reticulum - metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Pancreas - drug effects
Pancreas - metabolism
Tumor Cells, Cultured
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Summary:Store-operated Ca entry (SOCE), an important Ca 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 (IP Rs), sarco/endoplasmic reticulum Ca -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 Ca -store content at concentrations required for complete SOCE inhibition. DPB162-AE increased the cytosolic Ca levels by reducing the ER Ca store in cell lines as well as in primary cells. DPB162-AE did not affect SERCA activity, but provoked a Ca leak from the ER, even after application of the SERCA inhibitor thapsigargin. IP Rs partly contributed to the DPB162-AE-induced Ca leak, since pharmacologically and genetically inhibiting IP R 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 Ca -store content by inducing a Ca -leak pathway at concentrations needed for adequate SOCE inhibition.
ISSN:1532-1991