Glutamine Synthetase Stability and Subcellular Distribution in Astrocytes Are Regulated by γ-Aminobutyric Type B Receptors

• Published in: The Journal of biological chemistry Vol. 289; no. 42; pp. 28808 - 28815
• Main Authors: Huyghe, Deborah, Nakamura, Yasuko, Terunuma, Miho, Faideau, Mathilde, Haydon, Philip, Pangalos, Menelas N., Moss, Stephen J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Astrocytes - cytology; Astrocytes - enzymology; Brain - metabolism; Cell Line; Cell Membrane - enzymology; Cell Membrane - metabolism; Cells, Cultured; Chlorocebus aethiops; COS Cells; Female; Gene Expression Regulation, Enzymologic; Glutamate-Ammonia Ligase - physiology; Glutamine - metabolism; Male; Mice; Neurobiology; Neurons - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Interaction Mapping; Receptors, GABA-B - metabolism; Subcellular Fractions; Synaptic Transmission; Neuroscience; Neurosciences; traff; Astrocytes; GABAB Receptors; Protein-Protein Interaction; Trafficking; Glutamine Synthase; Astrocyte; Glutamine Synthetase
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M114.583534

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.