The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) is the third element in capacitative calcium entry

Abstract

STIM1 and Orai1 are the main players in capacitative calcium entry (CCE). STIM1 senses [Ca(2+)] inside the endoplasmic reticulum (ER) and, when it decreases, opens Orai1, a store-operated calcium channel (SOC) in the plasma membrane that promotes Ca(2+) entry and increases cytosolic Ca(2+). The final destination of the entering Ca(2+) is the ER, which refills very efficiently (capacitatively) with it. We propose here that SERCA is the third element of CCE, to which is tightly coupled to favour rapid Ca(2+) pumping from the high Ca(2+) microdomains, generated at the SOC's mouth, to the ER. We find that, on depletion of the intracellular Ca(2+) stores, SERCA co-localizes with STIM1 at puncta. Adequate coupling of CCE and ER Ca(2+) pumping requires correct proportions of STIM1, Orai1 and SERCA. Overexpression of Orai1 decreased modestly Ca(2+) entry, but produced a dramatic fall of Ca(2+) uptake into ER, which was rescued by STIM1 co-expression or by increasing external Ca(2+). In permeabilized cells, Ca(2+) uptake into the ER was indistinguishable in the Orai1-expressing and in the control cells. We propose that excess Orai1 uncouples SERCA from Ca(2+) entry in the intact cell by disturbing the fine topology of Ca(2+) pumping complexes within the ER-plasma membrane junctions.

Calcium Cycling in Synthetic and Contractile Phasic or Tonic Vascular Smooth Muscle Cells

“…Since SOCs opening depends on Ca 2+ content of the store, one may suggest that SERCA participates to its regulation. Consistent with this, SOCs open up when the leak of Ca 2+ from intracellular stores is not compensated with SERCA activity; SERCA inhibitors such as thapsigargin which prevent Ca 2+ uptake are commonly used to chemically induce SOC currents; several works have established that SERCA can cluster with STIM1 and Orai1 in various cellular types [41,42]. A n 1042 aa; 114.8 kDa …”

Bidirectional Coupling between Ryanodine Receptors and Ca2+ Release-activated Ca2+ (CRAC) Channel Machinery Sustains Store-operated Ca2+ Entry in Human T Lymphocytes

“…It is established that translocation of STIM1 within the ER membrane to the ER-plasma membrane junctional sites, and formation of puncta following a decline in [Ca 2ϩ ] ER promotes STIM1 coupling with the CRAC channel pore-forming ORAI1 protein and CRAC channel opening (12,48,49,51,52). It was also shown that SERCA co-localize with STIM1 puncta following store depletion (53,54). Collectively, these observations suggest that following store depletion, SOCE via CRAC channels elevates [Ca 2ϩ ] i at the ER-plasma membrane junctional sites, whereas SERCA absorbs Ca 2ϩ that has entered the cell, resulting in an increase in [Ca 2ϩ ] ER .…”

Calcium Dysregulation and Homeostasis of Neural Calcium in the Molecular Mechanisms of Neurodegenerative Diseases Provide Multiple Targets for Neuroprotection

“…All these important functions are controlled by intra-ER free Ca 2þ , which integrates various signaling events and establishes a link between fast signaling, associated with ER Ca 2þ release=Ca 2þ uptake, and long-lasting adaptive responses relying primarily on the regulation of protein synthesis (14,22). Recently, SERCA has to been shown to be functionally coupled to the Ca 2þ sensor in the ER, called STIM, and Orai, a member of the TRP family, to allow efficient refilling of the ER (65).…”