Garcia-Alvarez, Gisela, Lu, Bo, Yap, Kenrick An Fu, Wong, Loo Chin, Thevathasan, Jervis Vermal, Lim, Lynette, Ji, Fang, Tan, Kia Wee, Mancuso, James J., Tang, Willcyn, Poon, Shou Yu, Augustine, Goerge J. and Fivaz, Marc ORCID: https://orcid.org/0000-0003-1003-7934 (2015) STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs. Molecular Biology of the Cell, 26 (6). pp. 1141-1159. ISSN 1059-1524 (Print), 1939-4586 (Online) (doi:10.1091/mbc.E14-07-1222)

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Abstract

STIMs (STIM1 and STIM2 in mammals) are transmembrane proteins that reside in the endoplasmic reticulum (ER) and regulate store-operated Ca2+ entry (SOCE). The function of STIMs in the brain is only beginning to be explored, and the relevance of SOCE in nerve cells is being debated. Here we identify STIM2 as a central organizer of excitatory synapses. STIM2, but not its paralogue STIM1, influences the formation of dendritic spines and shapes basal synaptic transmission in excitatory neurons. We further demonstrate that STIM2 is essential for cAMP/PKA-dependent phosphorylation of the AMPA receptor (AMPAR) subunit GluA1. cAMP triggers rapid migration of STIM2 to ER–plasma membrane (PM) contact sites, enhances recruitment of GluA1 to these ER-PM junctions, and promotes localization of STIM2 in dendritic spines. Both biochemical and imaging data suggest that STIM2 regulates GluA1 phosphorylation by coupling PKA to the AMPAR in a SOCE-independent manner. Consistent with a central role of STIM2 in regulating AMPAR phosphorylation, STIM2 promotes cAMP-dependent surface delivery of GluA1 through combined effects on exocytosis and endocytosis. Collectively our results point to a unique mechanism of synaptic plasticity driven by dynamic assembly of a STIM2 signaling complex at ER-PM contact sites.

Item Type:	Article
Uncontrolled Keywords:	AMPA receptors, Endoplasmic reticulum, Synaptic plasticity, Stim2, Trafficking
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Education, Health & Human Sciences > School of Human Sciences (HUM)
Last Modified:	09 Oct 2021 04:45
URI:	http://gala.gre.ac.uk/id/eprint/17888

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