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CRAC channel gating and its modulation by STIM1 and 2‐aminoethoxydiphenyl borate
Author(s) -
Ali Sher,
Xu Tao,
Xu Xiaolan
Publication year - 2016
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp273130
Subject(s) - orai1 , gating , stim1 , chemistry , biophysics , ion channel , kcsa potassium channel , transmembrane protein , conductance , membrane potential , transmembrane domain , membrane , biochemistry , receptor , biology , physics , condensed matter physics
Ca 2+ release‐activated Ca 2+ (CRAC) channels play an essential role in the immune system. The pore‐forming subunit, Orai1, is an important pharmacological target. Here, we summarize the recent discoveries on the structure–function relationship of Orai1, as well as its interaction with the native channel opener STIM1 and chemical modulator 2‐aminoethoxydiphenyl borate (2‐APB). We first introduce the critical structural elements of Orai1, which include a Ca 2+ accumulating region, ion selectivity filter, hydrophobic centre, basic region, extended transmembrane Orai1 N‐terminal (ETON) region, transmembrane (TM) regions 2 and 3, P245 bend, 263 SHK 265 hinge linker and L273–L276 hydrophobic patch. We then hypothesize the possible mechanisms by which STIM1 triggers the conformational transitions of TM regions and exquisitely shapes the ion conduction pathway during generation of the CRAC current ( I crac ) with high Ca 2+ selectivity. Finally, we propose mechanisms by which 2‐APB modulates I crac . On the STIM1‐activated Orai1 channel, a low dose of 2‐APB acts directly, dilating its extremely narrow pore diameter from 3.8 to 4.6 Å, increasing its unitary channel conductance, and potentiating the I crac . Further elucidation of the structure of the opened CRAC channel and a better understanding of structure–function relationship will benefit the future development of novel immune modulators.