Privileged coupling between Ca2+ entry through plasma membrane store-operated Ca2+ channels and the endoplasmic reticulum Ca2+ pump

The sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) is the third element of capacitative calcium entry. It colocalizes with STIM1 and Orai1 at puncta, where couples plasma membrane store-operated Ca(2+) channels (SOC) to Ca(2+) pumping into the ER. The efficiency of this calcium entry-calcium refilling (CECR) coupling is comparable to the classic excitation-response transduction mechanisms. This allows efficient filling of the endoplasmic reticulum (ER) with the Ca(2+) entering through SOC channels with little progression of the Ca(2+) wave towards the cell core. CECR coupling is very sensitive to changes in stoichiometry among STIM, Orai and SERCA, with excess Orai antagonizing ER refilling. ER takes up most of the calcium load that enters through SOC, whereas mitochondria take up a very small fraction. This difference is due to the spatial positioning with regard to SOC, the amplitude of the high Ca(2+) microdomains, and the differences in the Ca(2+) affinity of the uptake mechanisms.