Tags

Type your tag names separated by a space and hit enter

2-Aminoethoxydiphenyl Borate Potentiates CRAC Current by Directly Dilating the Pore of Open Orai1.
Sci Rep. 2016 07 04; 6:29304.SR

Abstract

2-Aminoethoxydiphenyl borate (2-APB) elicits potentiation current (Ip) on Ca(2+) release-activated Ca(2+) (CRAC) channels. An accurate investigation into this modulation mechanism would reveal how STIM1-dependent channel gating is enhanced, and benefit the future immune enhancer development. Here, we directly probed the pore diameter of CRAC channels and found that 2-APB enlarged the pore size of STIM1-activated Orai1 from 3.8 to 4.6 Å. We demonstrated that ions with small sizes, i.e., Ca(2+) and Na(+), mediated prominent 2-APB-induced Ip on the wildtype (WT) Orai1 channels of narrow pore sizes, while conducted decreased or no Ip on Orai1-V102C/A/G mutant channels with enlarged pore diameters. On the contrary, large Cs(+) ions blocked the WT channels, while displayed large 2-APB induced Ip on pore-enlarged Orai1-V102C/A/G mutant channels, and the potentiation ratio was highest on Orai1-V102C with an intermediate pore size. Furthermore, we showed that 2-APB potentiated Cs(+) current on constitutively active Orai1-V102C/A/G mutants independent of STIM1. Our data suggest that 2-APB directly dilates the pore of open Orai1 channels, both ion size and pore diameter jointly determine the amplitude of Ip on CRAC channels, and the generation of Ip requires the open state of Orai1, not STIM1 itself.

Authors+Show Affiliations

National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. University of Chinese Academy of Science, Beijing 100049, China.National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. College of Life Science, Sichuan Normal University, Chengdu 610101, China.Department of Physiology and Biophysics, University of Washington, Seattle, WA, USA.Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27373367

Citation

Xu, Xiaolan, et al. "2-Aminoethoxydiphenyl Borate Potentiates CRAC Current By Directly Dilating the Pore of Open Orai1." Scientific Reports, vol. 6, 2016, p. 29304.
Xu X, Ali S, Li Y, et al. 2-Aminoethoxydiphenyl Borate Potentiates CRAC Current by Directly Dilating the Pore of Open Orai1. Sci Rep. 2016;6:29304.
Xu, X., Ali, S., Li, Y., Yu, H., Zhang, M., Lu, J., & Xu, T. (2016). 2-Aminoethoxydiphenyl Borate Potentiates CRAC Current by Directly Dilating the Pore of Open Orai1. Scientific Reports, 6, 29304. https://doi.org/10.1038/srep29304
Xu X, et al. 2-Aminoethoxydiphenyl Borate Potentiates CRAC Current By Directly Dilating the Pore of Open Orai1. Sci Rep. 2016 07 4;6:29304. PubMed PMID: 27373367.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 2-Aminoethoxydiphenyl Borate Potentiates CRAC Current by Directly Dilating the Pore of Open Orai1. AU - Xu,Xiaolan, AU - Ali,Sher, AU - Li,Yufeng, AU - Yu,Haijie, AU - Zhang,Mingshu, AU - Lu,Jingze, AU - Xu,Tao, Y1 - 2016/07/04/ PY - 2016/01/07/received PY - 2016/06/17/accepted PY - 2016/7/5/entrez PY - 2016/7/5/pubmed PY - 2018/6/13/medline SP - 29304 EP - 29304 JF - Scientific reports JO - Sci Rep VL - 6 N2 - 2-Aminoethoxydiphenyl borate (2-APB) elicits potentiation current (Ip) on Ca(2+) release-activated Ca(2+) (CRAC) channels. An accurate investigation into this modulation mechanism would reveal how STIM1-dependent channel gating is enhanced, and benefit the future immune enhancer development. Here, we directly probed the pore diameter of CRAC channels and found that 2-APB enlarged the pore size of STIM1-activated Orai1 from 3.8 to 4.6 Å. We demonstrated that ions with small sizes, i.e., Ca(2+) and Na(+), mediated prominent 2-APB-induced Ip on the wildtype (WT) Orai1 channels of narrow pore sizes, while conducted decreased or no Ip on Orai1-V102C/A/G mutant channels with enlarged pore diameters. On the contrary, large Cs(+) ions blocked the WT channels, while displayed large 2-APB induced Ip on pore-enlarged Orai1-V102C/A/G mutant channels, and the potentiation ratio was highest on Orai1-V102C with an intermediate pore size. Furthermore, we showed that 2-APB potentiated Cs(+) current on constitutively active Orai1-V102C/A/G mutants independent of STIM1. Our data suggest that 2-APB directly dilates the pore of open Orai1 channels, both ion size and pore diameter jointly determine the amplitude of Ip on CRAC channels, and the generation of Ip requires the open state of Orai1, not STIM1 itself. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/27373367/2_Aminoethoxydiphenyl_Borate_Potentiates_CRAC_Current_by_Directly_Dilating_the_Pore_of_Open_Orai1_ L2 - http://dx.doi.org/10.1038/srep29304 DB - PRIME DP - Unbound Medicine ER -