Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs

Eunan Hendron, Xizhuo Wang, Yandong Zhou, Xiangyu Cai, Jun Ichi Goto, Katsuhiko Mikoshiba, Yoshihiro Baba, Tomohiro Kurosaki, Youjun Wang, Donald L. Gill

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The coupling of ER Ca2+-sensing STIM proteins and PM Orai Ca2+ entry channels generates "store-operated" Ca2+ signals crucial in controlling responses in many cell types. The dimeric derivative of 2-aminoethoxydiphenyl borinate (2-APB), DPB162-AE, blocks functional coupling between STIM1 and Orai1 with an IC50 (200nM) 100-fold lower than 2-APB. Unlike 2-APB, DPB162-AE does not affect L-type or TRPC channels or Ca2+ pumps at maximal STIM1-Orai1 blocking levels. DPB162-AE blocks STIM1-induced Orai1 or Orai2, but does not block Orai3 or STIM2-mediated effects. We narrowed the DPB162-AE site of action to the STIM-Orai activating region (SOAR) of STIM1. DPB162-AE does not prevent the SOAR-Orai1 interaction but potently blocks SOAR-mediated Orai1 channel activation, yet its action is not as an Orai1 channel pore blocker. Using the SOAR-F394H mutant which prevents both physical and functional coupling to Orai1, we reveal DPB162-AE rapidly restores SOAR-Orai binding but only slowly restores Orai1 channel-mediated Ca2+ entry. With the same SOAR mutant, 2-APB induces rapid physical and functional coupling to Orai1, but channel activation is transient. We infer that the actions of both 2-APB and DPB162-AE are directed toward the STIM1-Orai1 coupling interface. Compared to 2-APB, DPB162-AE is a much more potent and specific STIM1/Orai1 functional uncoupler. DPB162-AE provides an important pharmacological tool and a useful mechanistic probe for the function and coupling between STIM1 and Orai1 channels.

Original languageEnglish
Pages (from-to)482-492
Number of pages11
JournalCell Calcium
Volume56
Issue number6
DOIs
Publication statusPublished - Jan 1 2014
Externally publishedYes

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DPB162-AE
2-aminodiphenyl
Inhibitory Concentration 50
Pharmacology
Proteins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Hendron, E., Wang, X., Zhou, Y., Cai, X., Goto, J. I., Mikoshiba, K., ... Gill, D. L. (2014). Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. Cell Calcium, 56(6), 482-492. https://doi.org/10.1016/j.ceca.2014.10.005

Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. / Hendron, Eunan; Wang, Xizhuo; Zhou, Yandong; Cai, Xiangyu; Goto, Jun Ichi; Mikoshiba, Katsuhiko; Baba, Yoshihiro; Kurosaki, Tomohiro; Wang, Youjun; Gill, Donald L.

In: Cell Calcium, Vol. 56, No. 6, 01.01.2014, p. 482-492.

Research output: Contribution to journalArticle

Hendron, E, Wang, X, Zhou, Y, Cai, X, Goto, JI, Mikoshiba, K, Baba, Y, Kurosaki, T, Wang, Y & Gill, DL 2014, 'Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs', Cell Calcium, vol. 56, no. 6, pp. 482-492. https://doi.org/10.1016/j.ceca.2014.10.005
Hendron, Eunan ; Wang, Xizhuo ; Zhou, Yandong ; Cai, Xiangyu ; Goto, Jun Ichi ; Mikoshiba, Katsuhiko ; Baba, Yoshihiro ; Kurosaki, Tomohiro ; Wang, Youjun ; Gill, Donald L. / Potent functional uncoupling between STIM1 and Orai1 by dimeric 2-aminodiphenyl borinate analogs. In: Cell Calcium. 2014 ; Vol. 56, No. 6. pp. 482-492.
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AU - Cai, Xiangyu

AU - Goto, Jun Ichi

AU - Mikoshiba, Katsuhiko

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