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2-Aminoethoxydiphenyl borate (2-APB) elicits potentiation current ( I   p  ) 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  I   p   on the wildtype (WT) Orai1 channels of narrow pore sizes, while conducted decreased or no  I   p   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  I   p   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  I   p   on CRAC channels, and the generation of  I   p   requires the open state of Orai1, not STIM1 itself.

2-Aminoethoxydiphenyl Borate Potentiates CRAC Current by Directly Dilating the Pore of Open Orai1