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

Emerging evidence suggests that functional gamma-aminobutyric acid B receptors (GABA(B)Rs) are expressed by astrocytes within the mammalian brain. GABA(B)Rs 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 GABA(B)R2 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 GABA(B)R2 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 GABA(B)R2 occurs via reduced proteasomal degradation. Collectively, our results suggest a novel role for GABA(B)Rs as regulators of GS stability. Given the critical role that GS plays in the glutamineglutamate cycle, astrocytic GABA(B)Rs may play a critical role in supporting both inhibitory and excitatory neurotransmission.