Spatially restricted subcellular Ca signaling downstream of store-operated calcium entry encoded by a cortical tunneling mechanism.

Agonist-dependent Ca mobilization results in Ca store depletion and Store-Operated Calcium Entry (SOCE), which is spatially restricted to microdomains defined by cortical ER - plasma membrane contact sites (MCS). However, some Ca-dependent effectors that localize away from SOCE microdomains, are activated downstream of SOCE by mechanisms that remain obscure. One mechanism proposed initially in acinar cells and termed Ca tunneling, mediates the uptake of Ca flowing through SOCE into the ER followed by release at distal sites through IP receptors. Here we show that Ca tunneling encodes exquisite specificity downstream of SOCE signal by dissecting the sensitivity and dependence of multiple effectors in HeLa cells. While mitochondria readily perceive Ca release when stores are full, SOCE shows little effect in raising mitochondrial Ca, and Ca-tunneling is completely inefficient. In contrast, gK displays a similar sensitivity to Ca release and tunneling, while the activation of NFAT1 is selectively responsive to SOCE and not to Ca release. These results show that in contrast to the previously described long-range Ca tunneling, in non-specialized HeLa cells this mechanism mediates spatially restricted Ca rise within the cortical region of the cell to activate a specific subset of effectors.