title: Two novel 2-aminoethyl diphenylborinate (2-APB) analogues differentially activate and inhibit store-operated Ca(2+) entry via STIM proteins.
abstract: Store-operated calcium entry (SOCE) or calcium release-activated calcium current (I(CRAC)) is a critical pathway to replenish intracellular calcium stores, and plays indispensable roles in cellular functions such as antigen-induced T lymphocyte activation. Despite the importance of I(CRAC) in cellular functions, lack of potent and specific inhibitor has limited the approaches to the function of I(CRAC) in native cells. 2-Aminoethyl diphenylborinate (2-APB) is a widely used SOCE/I(CRAC) inhibitor, while its effect is rather unspecific. In the attempt to develop more potent and selective compounds here we identified two structurally isomeric 2-APB analogues that are 100-fold more potent than 2-APB itself. One of the 2-APB analogues activates and inhibits endogenous SOCE depending on the concentration while the other only inhibits it. The 2-APB analogue inhibits store depletion-mediated STIM1 clustering as well as heterologously expressed CRAC current. Together with the observation that, unlike 2-APB, the analogue compounds failed to activate CRACM3/Orai3 current in the absence of STIM, our results suggest that inhibition and activation of SOCE/I(CRAC) by the 2-APB analogues is mediated by STIM.
authors: Brain Science Institute, RIKEN, Wako, Saitama, Japan.
authors: Jun-Ichi
authors: J
authors: Goto
authors: Akinobu Z
authors: AZ
authors: Suzuki
authors: Shoichiro
authors: S
authors: Ozaki
authors: Nagisa
authors: N
authors: Matsumoto
authors: Takeshi
authors: T
authors: Nakamura
authors: Etsuko
authors: E
authors: Ebisui
authors: Andrea
authors: A
authors: Fleig
authors: Reinhold
authors: R
authors: Penner
authors: Katsuhiko
authors: K
authors: Mikoshiba
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002645:Chickens; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D019169:Jurkat Cells; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; D015220:Calcium Channels; C000599936:DPB162-AE; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C522867:Orai3 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels