Spatially restricted subcellular Ca<sup>2+</sup> signaling downstream of store-operated calcium entry encoded by a cortical tunneling mechanism.

Overview

Agonist-dependent Ca²⁺ mobilization results in Ca²⁺ 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 Ca²⁺-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 Ca²⁺ tunneling, mediates the uptake of Ca²⁺ flowing through SOCE into the ER followed by release at distal sites through IP₃ receptors. Here we show that Ca²⁺ tunneling encodes exquisite specificity downstream of SOCE signal by dissecting the sensitivity and dependence of multiple effectors in HeLa cells. While mitochondria readily perceive Ca²⁺ release when stores are full, SOCE shows little effect in raising mitochondrial Ca²⁺, and Ca²⁺-tunneling is completely inefficient. In contrast, gK_Ca displays a similar sensitivity to Ca²⁺ release and tunneling, while the activation of NFAT1 is selectively responsive to SOCE and not to Ca²⁺ release. These results show that in contrast to the previously described long-range Ca²⁺ tunneling, in non-specialized HeLa cells this mechanism mediates spatially restricted Ca²⁺ rise within the cortical region of the cell to activate a specific subset of effectors.