Calcium Tunneling: A Pervasive Signaling Module Mediated by Coupling Store-Operated Ca ²⁺ Entry and Endoplasmic Reticulum Ca ²⁺ Release

The ability of the cell to generate precise and sustained intracellular Ca²⁺ signals is governed by multiple spatial and temporal restrictions. Ca²⁺ flowing into the cell through plasma membrane channels activates multiple effectors but is limited to targets in the vicinity of the channel. To reach distant effectors, cells developed a mechanism termed "Ca²⁺ tunneling" where extracellular Ca²⁺ entering the cell through "store-operated Ca²⁺ entry" is shuttled through the lumen of the cortical endoplasmic reticulum to be released by inositol 1,4,5-trisphosphate receptors toward distal targets. Here, we review the mechanisms and functions of Ca²⁺ tunneling in light of recent findings linking the structure of the cortical endoplasmic reticulum at membrane contact sites and the organization of the tunneling machinery.