title: Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions.
abstract: 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.
authors.affiliation: Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chi-Lun
authors.initials: CL
authors.lastname: Chang
authors.forename: Ting-Sung
authors.initials: TS
authors.lastname: Hsieh
authors.forename: T Tony
authors.initials: TT
authors.lastname: Yang
authors.forename: Karen G
authors.initials: KG
authors.lastname: Rothberg
authors.forename: D Berfin
authors.initials: DB
authors.lastname: Azizoglu
authors.forename: Elzibeth
authors.initials: E
authors.lastname: Volk
authors.forename: Jung-Chi
authors.initials: JC
authors.lastname: Liao
authors.forename: Jen
authors.initials: J
authors.lastname: Liou
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008854:Microscopy, Electron; D015398:Signal Transduction; D050857:Synaptotagmins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D002135:Calcium-Binding Proteins; C583132:ESYT1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; C113505:PITPNM1 protein, human; D050857:Synaptotagmins; D002118:Calcium