Research ArticleCell Biology

STIM2 enhances receptor-stimulated Ca2+ signaling by promoting recruitment of STIM1 to the endoplasmic reticulum–plasma membrane junctions

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Science Signaling  13 Jan 2015:
Vol. 8, Issue 359, pp. ra3
DOI: 10.1126/scisignal.2005748

Escorting the Sensor to the Channel

Receptors that trigger the release of calcium from the endoplasmic reticulum (ER) regulate various physiological processes, including fluid secretion from salivary glands. This type of calcium signaling requires calcium influx stimulated by depletion of calcium, stored in the ER, through a process involving calcium sensor protein STIM1 in the ER and the channel Orai1 at the plasma membrane. Ong et al. found that STIM2, a protein related to STIM1, helped traffic STIM1 to the junctions where the ER and plasma membrane are closely apposed, so that calcium entry through Orai1 is initiated in response to lower amounts of stimulation. The researchers showed that mice lacking STIM2 had reduced fluid secretion from their salivary glands.


A central component of receptor-evoked Ca2+ signaling is store-operated Ca2+ entry (SOCE), which is activated by the assembly of STIM1-Orai1 channels in endoplasmic reticulum (ER) and plasma membrane (PM) (ER-PM) junctions in response to depletion of ER Ca2+. We report that STIM2 enhances agonist-mediated activation of SOCE by promoting STIM1 clustering in ER-PM junctions at low stimulus intensities. Targeted deletion of STIM2 in mouse salivary glands diminished fluid secretion in vivo and SOCE activation in dispersed salivary acinar cells stimulated with low concentrations of muscarinic receptor agonists. STIM2 knockdown in human embryonic kidney (HEK) 293 cells diminished agonist-induced Ca2+ signaling and nuclear translocation of NFAT (nuclear factor of activated T cells). STIM2 lacking five carboxyl-terminal amino acid residues did not promote formation of STIM1 puncta at low concentrations of agonist, whereas coexpression of STIM2 with STIM1 mutant lacking the polybasic region STIM1ΔK resulted in co-clustering of both proteins. Together, our findings suggest that STIM2 recruits STIM1 to ER-PM junctions at low stimulus intensities when ER Ca2+ stores are mildly depleted, thus increasing the sensitivity of Ca2+ signaling to agonists.

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