InsP(3) receptors and Orai channels in pancreatic acinar cells: co-localization and its consequences

Orai1 proteins have been recently identified as subunits of SOCE (store-operated Ca(2+) entry) channels. In primary isolated PACs (pancreatic acinar cells), Orai1 showed remarkable co-localization and co-immunoprecipitation with all three subtypes of IP(3)Rs (InsP(3) receptors). The co-localization between Orai1 and IP(3)Rs was restricted to the apical part of PACs. Neither co-localization nor co-immunoprecipitation was affected by Ca(2+) store depletion. Importantly we also characterized Orai1 in basal and lateral membranes of PACs. The basal and lateral membranes of PACs have been shown previously to accumulate STIM1 (stromal interaction molecule 1) puncta as a result of Ca(2+) store depletion. We therefore conclude that these polarized secretory cells contain two pools of Orai1: an apical pool that interacts with IP(3)Rs and a basolateral pool that interacts with STIM1 following the Ca(2+) store depletion. Experiments on IP(3)R knockout animals demonstrated that the apical Orai1 localization does not require IP(3)Rs and that IP(3)Rs are not necessary for the activation of SOCE. However, the InsP(3)-releasing secretagogue ACh (acetylcholine) produced a negative modulatory effect on SOCE, suggesting that activated IP(3)Rs could have an inhibitory effect on this Ca(2+) entry mechanism.