Abstract
Agonist-dependent Ca(2+) mobilization results in Ca(2+) 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(2+)-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(2+) tunneling, mediates the uptake of Ca(2+) flowing through SOCE into the ER followed by release at distal sites through IP(3) receptors. Here we show that Ca(2+) 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(2+) release when stores are full, SOCE shows little effect in raising mitochondrial Ca(2+), and Ca(2+)-tunneling is completely inefficient. In contrast, gK(Ca) displays a similar sensitivity to Ca(2+) release and tunneling, while the activation of NFAT1 is selectively responsive to SOCE and not to Ca(2+) release. These results show that in contrast to the previously described long-range Ca(2+) tunneling, in non-specialized HeLa cells this mechanism mediates spatially restricted Ca(2+) rise within the cortical region of the cell to activate a specific subset of effectors.