Mid-range Ca2+ signalling mediated by functional coupling between store-operated Ca2+ entry and IP3-dependent Ca2+ release.

The versatility and universality of Ca(2+) signals stem from the breadth of their spatial and temporal dynamics. Spatially, Ca(2+) signalling is well studied in the microdomain scale, close to a Ca(2+) channel, and at the whole-cell level. However, little is known about how local Ca(2+) signals are regulated to specifically activate spatially distant effectors without a global Ca(2+) rise. Here we show that an intricate coupling between the inositol 1,4,5 trisphosphate (IP3) receptor, SERCA pump and store-operated Ca(2+) entry (SOCE) allows for efficient mid-range Ca(2+) signalling. Ca(2+) flowing through SOCE is taken up into the ER lumen by the SERCA pump, only to be re-released by IP3Rs to activate distal Ca(2+)-activated Cl(-) channels (CaCCs). This CaCC regulation contributes to setting the membrane potential of the cell. Hence functional coupling between SOCE, SERCA and IP3R limits local Ca(2+) diffusion and funnels Ca(2+) through the ER lumen to activate a spatially separate Ca(2+) effector.