title: 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.
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, 3000 Leuven, Belgium.
authors.forename: Mart
authors.initials: M
authors.lastname: Bittremieux
authors.affiliation: Cardiff University, MCR Secretory Control Research Group, Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, Wales, UK.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Gerasimenko
authors.affiliation: KU Leuven, Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, 3000 Leuven, Belgium.
authors.forename: Marleen
authors.initials: M
authors.lastname: Schuermans
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, 3000 Leuven, Belgium.
authors.forename: Tomas
authors.initials: T
authors.lastname: Luyten
authors.affiliation: Cardiff University, MCR Secretory Control Research Group, Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, Wales, UK.
authors.forename: Eloise
authors.initials: E
authors.lastname: Stapleton
authors.affiliation: University of Rochester, Department of Pharmacology and Physiology, Rochester, NY 14642, USA.
authors.forename: Kamil J
authors.initials: KJ
authors.lastname: Alzayady
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, 3000 Leuven, Belgium.
authors.forename: Humbert
authors.initials: H
authors.lastname: De Smedt
authors.affiliation: University of Rochester, Department of Pharmacology and Physiology, Rochester, NY 14642, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Yule
authors.affiliation: The Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.affiliation: KU Leuven, Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vangheluwe
authors.affiliation: Cardiff University, MCR Secretory Control Research Group, Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, Wales, UK.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Gerasimenko
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, 3000 Leuven, Belgium.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Parys
authors.affiliation: KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, 3000 Leuven, Belgium. Electronic address: geert.bultynck@kuleuven.be.
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D001896:Boron Compounds; C000599936:DPB162-AE; D002118:Calcium
keywords: 2-APB analogue; Ca(2+)-leak pathway; Calcium; DPB162-AE; Endoplasmic reticulum; Store-operated Ca(2+) entry