title: STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs.
abstract: STIMs (STIM1 and STIM2 in mammals) are transmembrane proteins that reside in the endoplasmic reticulum (ER) and regulate store-operated Ca(2+) 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.
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Gisela
authors.initials: G
authors.lastname: Garcia-Alvarez
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Kenrick An Fu
authors.initials: KA
authors.lastname: Yap
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Loo Chin
authors.initials: LC
authors.lastname: Wong
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Jervis Vermal
authors.initials: JV
authors.lastname: Thevathasan
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Lynette
authors.initials: L
authors.lastname: Lim
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Fang
authors.initials: F
authors.lastname: Ji
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Kia Wee
authors.initials: KW
authors.lastname: Tan
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: James J
authors.initials: JJ
authors.lastname: Mancuso
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Willcyn
authors.initials: W
authors.lastname: Tang
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857.
authors.forename: Shou Yu
authors.initials: SY
authors.lastname: Poon
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 637553 Center for Functional Connectomics, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
authors.forename: George J
authors.initials: GJ
authors.lastname: Augustine
authors.affiliation: Program in Neuroscience and Behavioral Disorders, DUKE-NUS Graduate Medical School, Singapore 169857 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597 marc.fivaz@duke-nus.edu.sg.
authors.forename: Marc
authors.initials: M
authors.lastname: Fivaz
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D049229:Dendritic Spines / Q000502:physiology; D004705:Endocytosis; D005089:Exocytosis; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D009473:Neuronal Plasticity; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D000071738:Stromal Interaction Molecule 2
chemical_list: D002135:Calcium-Binding Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D008565:Membrane Proteins; D018091:Receptors, AMPA; D000071738:Stromal Interaction Molecule 2; C560435:STIM2 protein, rat