title: Glutamine synthetase stability and subcellular distribution in astrocytes are regulated by γ-aminobutyric type B receptors.
abstract: Emerging evidence suggests that functional γ-aminobutyric acid B receptors (GABABRs) are expressed by astrocytes within the mammalian brain. GABABRs are heterodimeric G-protein-coupled receptors that are composed of R1/R2 subunits. To date, they have been characterized in neurons as the principal mediators of sustained inhibitory signaling; however their roles in astrocytic physiology have been ill defined. Here we reveal that the cytoplasmic tail of the GABABR2 subunit binds directly to the astrocytic protein glutamine synthetase (GS) and that this interaction determines the subcellular localization of GS. We further demonstrate that the binding of GS to GABABR2 increases the steady state expression levels of GS in heterologous cells and in mouse primary astrocyte culture. Mechanistically this increased stability of GS in the presence of GABABR2 occurs via reduced proteasomal degradation. Collectively, our results suggest a novel role for GABABRs as regulators of GS stability. Given the critical role that GS plays in the glutamine-glutamate cycle, astrocytic GABABRs may play a critical role in supporting both inhibitory and excitatory neurotransmission.
authors.affiliation: From the Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Deborah
authors.initials: D
authors.lastname: Huyghe
authors.affiliation: From the Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Cell Physiology and Pharmacology, College of Medicine, Biological Sciences and Psychology, University of Leicester, University Road, Leicester LE1 9HN, United Kingdom.
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.affiliation: Department of Experimental Dementia Research, Lund University SE-221 00 Lund, Sweden.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Faideau
authors.affiliation: From the Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111.
authors.forename: Philip
authors.initials: P
authors.lastname: Haydon
authors.affiliation: Innovative Medicines, AstraZeneca, Mereside, Alderley Park, Cheshire SK10 4TF, United Kingdom, and.
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.affiliation: From the Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, Department of Neuroscience, Physiology & Pharmacology, University College London, London WC1E 6B, United Kingdom Stephen.Moss@Tufts.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology*; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005974:Glutamate-Ammonia Ligase / Q000502:physiology*; D005973:Glutamine / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025941:Protein Interaction Mapping; D018080:Receptors, GABA-B / Q000378:metabolism*; D013347:Subcellular Fractions; D009435:Synaptic Transmission
chemical_list: C485504:Gabbr2 protein, mouse; D018080:Receptors, GABA-B; D005973:Glutamine; D046988:Proteasome Endopeptidase Complex; D005974:Glutamate-Ammonia Ligase
keywords: Astrocyte; Astrocytes; GABAB Receptors; Glutamine Synthase; Glutamine Synthetase; Neuroscience; Neurosciences; Protein-Protein Interaction; Trafficking; traff