STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation.

Parvez, Suhel; Beck, Andreas; Peinelt, Christine; Soboloff, Jonathan; Lis, Annette; Monteilh-Zoller, Mahealani; Gill, Donald L; Fleig, Andrea; Penner, Reinhold (2008). STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB journal, 22(3), pp. 752-761. Federation of American Societies for Experimental Biology 10.1096/fj.07-9449com

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STIM1 and CRACM1 (or Orai1) are essential molecular components mediating store-operated Ca2+ entry (SOCE) and Ca2+ release-activated Ca2+ (CRAC) currents. Although STIM1 acts as a luminal Ca2+ sensor in the endoplasmic reticulum (ER), the function of STIM2 remains unclear. Here we reveal that STIM2 has two distinct modes of activating CRAC channels: a store-operated mode that is activated through depletion of ER Ca2+ stores by inositol 1,4,5-trisphosphate (InsP3) and store-independent activation that is mediated by cell dialysis during whole-cell perfusion. Both modes are regulated by calmodulin (CaM). The store-operated mode is transient in intact cells, possibly reflecting recruitment of CaM, whereas loss of CaM in perfused cells accounts for the persistence of the store-independent mode. The inhibition by CaM can be reversed by 2-aminoethoxydiphenyl borate (2-APB), resulting in rapid, store-independent activation of CRAC channels. The aminoglycoside antibiotic G418 is a highly specific and potent inhibitor of STIM2-dependent CRAC channel activation. The results reveal a novel bimodal control of CRAC channels by STIM2, the store dependence and CaM regulation, which indicates that the STIM2/CRACM1 complex may be under the control of both luminal and cytoplasmic Ca2+ levels.

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