Two novel 2-aminoethyl diphenylborinate (2-APB) analogues differentially activate and inhibit store-operated Ca2+ entry via STIM proteins

Jun Ichi Goto, Akinobu Z. Suzuki, Shoichiro Ozaki, Nagisa Matsumoto, Takeshi Nakamura, Etsuko Ebisui, Andrea Fleig, Reinhold Penner, Katsuhiko Mikoshiba

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Abstract

Store-operated calcium entry (SOCE) or calcium release-activated calcium current (ICRAC) 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 ICRAC in cellular functions, lack of potent and specific inhibitor has limited the approaches to the function of ICRAC in native cells. 2-Aminoethyl diphenylborinate (2-APB) is a widely used SOCE/ICRAC 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/ICRAC by the 2-APB analogues is mediated by STIM.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalCell Calcium
Volume47
Issue number1
DOIs
Publication statusPublished - 2010 Jan
Externally publishedYes

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Keywords

  • 2-APB
  • Calcium
  • CRAC
  • CRACM
  • Orai
  • STIM
  • Store-operated calcium entry

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Goto, J. I., Suzuki, A. Z., Ozaki, S., Matsumoto, N., Nakamura, T., Ebisui, E., Fleig, A., Penner, R., & Mikoshiba, K. (2010). Two novel 2-aminoethyl diphenylborinate (2-APB) analogues differentially activate and inhibit store-operated Ca2+ entry via STIM proteins. Cell Calcium, 47(1), 1-10. https://doi.org/10.1016/j.ceca.2009.10.004