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Cell Rep. 2013 Nov 14;5(3):813-25. doi: 10.1016/j.celrep.2013.09.038. Epub 2013 Oct 31.

Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions.

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Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.


Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are highly conserved subcellular structures. Despite their importance in Ca(2+) signaling and lipid trafficking, the molecular mechanisms underlying the regulation and functions of ER-PM junctions remain unclear. By developing a genetically encoded marker that selectively monitors ER-PM junctions, we found that the connection between ER and PM was dynamically regulated by Ca(2+) signaling. Elevation of cytosolic Ca(2+) triggered translocation of E-Syt1 to ER-PM junctions to enhance ER-to-PM connection. This subsequently facilitated the recruitment of Nir2, a phosphatidylinositol transfer protein (PITP), to ER-PM junctions following receptor stimulation. Nir2 promoted the replenishment of PM phosphatidylinositol 4,5-bisphosphate (PIP2) after receptor-induced hydrolysis via its PITP activity. Disruption of the enhanced ER-to-PM connection resulted in reduced PM PIP2 replenishment and defective Ca(2+) signaling. Altogether, our results suggest a feedback mechanism that replenishes PM PIP2 during receptor-induced Ca(2+) signaling via the Ca(2+) effector E-Syt1 and the PITP Nir2 at ER-PM junctions.

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