Ca2+ tunnelling through the ER lumen as a mechanism for delivering Ca2+ entering via store‐operated Ca2+ channels to specific target sites

Ca2+ signalling is perhaps the most universal and versatile mechanism regulating a wide range of cellular processes. Because of the many different calcium‐binding proteins distributed throughout cells, signalling precision requires localized rises in the cytosolic Ca2+ concentration. In electrically non‐excitable cells, for example epithelial cells, this is achieved by primary release of Ca2+ from the endoplasmic reticulum via Ca2+ release channels placed close to the physiological target. Because any rise in the cytosolic Ca2+ concentration activates Ca2+ extrusion, and in order for cells not to run out of Ca2+, there is a need for compensatory Ca2+ uptake from the extracellular fluid. This Ca2+ uptake occurs through a process known as store‐operated Ca2+ entry. Ideally Ca2+ entering the cell should not diffuse to the target site through the cytosol, as this would potentially activate undesirable processes. Ca2+ tunnelling through the lumen of the endoplasmic reticulum is a mechanism for delivering Ca2+ entering via store‐operated Ca2+ channels to specific target sites, and this process has been described in considerable detail in pancreatic acinar cells and oocytes. Here we review the most important evidence and present a generalized concept. The figure illustrates the principle by which Ca2+ tunnelling through the lumen of the endoplasmic reticulum (ER) can deliver Ca2+ entering through store‐operated Ca2+ channels (Orai1) to a site remote from the entry site, thereby activating a specific physiological process (Ca2+‐sensitive Cl− channels (ANO1)) via release through IP3 receptors (IP3R) placed close to the target. The primary step is Ca2+ release from the ER via IP3R caused by agonist stimulation, which generates IP3 (not shown in the figure). This causes a reduction in the Ca2+ concentration in the ER lumen, which triggers translocation of STIM1 molecules in the ER membrane, so that they come very close to Ca2+ entry channels and activate these. Ca2+ entering through the Orai1 channels is immediately taken up into the ER by powerful Ca2+ pumps (SERCA) and move with relative ease through the ER lumen by simple diffusion. The mobility of Ca2+ in the ER lumen is significantly higher than in the cytosol due to the much lower Ca2+ binding capacity.