The increase in intracellular Ca2+ through the Ca2+ channel is an indispensable step for the secretion of inflammatory mediators by mast cells. It was recently reported that Orai-1 is responsible for the Ca2+ influx that is activated by depletion of stored Ca2+. There are three isoforms of Orai: orai-1, Orai-2, and Orai-3; however, isoforms other than orai-1 are poorly understood. We found that Orai-2 is expressed and localized on secretory granules in RBL-2H3. Ca2+ release from Ca2+ store, induced by antigen stimulation, was significantly attenuated by knockdown of Orai-2, while that induced by thapsigargin was not affected. Furthermore, exocytotic release induced by antigen stimulation was inhibited in knockdown cells. This observation suggests a new role of orai isoforms in secretory cells. (C) 2014 Elsevier Inc. All rights reserved.