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

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