Feedback Regulation of Receptor-Induced Ca2+ Signaling Mediated by E-Syt1 and Nir2 at Endoplasmic Reticulum-Plasma Membrane Junctions

• Published in: Cell reports (Cambridge) Vol. 5; no. 3; pp. 813 - 825
• Main Authors: Chang, Chi-Lun, Hsieh, Ting-Sung, Yang, T. Tony, Rothberg, Karen G., Azizoglu, D. Berfin, Volk, Elzibeth, Liao, Jung-Chi, Liou, Jen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013; Elsevier
• Subjects: Calcium - metabolism; Calcium Signaling; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cell Culture Techniques; Endoplasmic Reticulum - metabolism; Eye Proteins - genetics; Eye Proteins - metabolism; HeLa Cells; Humans; Jurkat Cells; Membrane Proteins - genetics; Membrane Proteins - metabolism; Microscopy, Electron; Signal Transduction; Synaptotagmins - genetics; Synaptotagmins - metabolism; Transfection
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.09.038

Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are highly conserved subcellular structures. Despite their importance in Ca2+ 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 Ca2+ signaling. Elevation of cytosolic Ca2+ 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 Ca2+ signaling. Altogether, our results suggest a feedback mechanism that replenishes PM PIP2 during receptor-induced Ca2+ signaling via the Ca2+ effector E-Syt1 and the PITP Nir2 at ER-PM junctions. [Display omitted] •A marker is developed for studying the regulation and functions of ER-PM junctions•Ca2+-induced E-Syt1 translocation to ER-PM junctions enhances ER-PM connection•An enhanced ER-PM connection facilitates Nir2 recruitment to ER-PM junctions•Nir2 promotes PM PIP2 replenishment following receptor-induced hydrolysis The regulation and functions of endoplasmic reticulum (ER)-plasma membrane (PM) junctions are poorly understood. By developing a marker for ER-PM junctions, Liou and colleagues show that ER-PM connection is enhanced during Ca2+ signaling by E-Syt1. E-Syt1-mediated enhanced ER-PM connection facilitates the recruitment of a phosphatidylinositol transfer protein Nir2 to ER-PM junctions, resulting in replenishment of PM phosphatidylinositol 4,5-bisphosphate (PIP2) following receptor-induced hydrolysis. The study reveals a feedback mechanism at ER-PM junctions that replenishes PM PIP2 during receptor-induced Ca2+ signaling.