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

Abstract:

: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.

journal_name

Cell Calcium

journal_title

Cell calcium

authors

Bittremieux M,Gerasimenko JV,Schuermans M,Luyten T,Stapleton E,Alzayady KJ,De Smedt H,Yule DI,Mikoshiba K,Vangheluwe P,Gerasimenko OV,Parys JB,Bultynck G

doi

10.1016/j.ceca.2017.01.015

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

60-70

eissn

0143-4160

issn

1532-1991

pii

S0143-4160(16)30207-X

journal_volume

62

pub_type

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