title: Differential regulation of GABAB receptor trafficking by different modes of N-methyl-D-aspartate (NMDA) receptor signaling.
abstract: Inhibitory GABAB receptors (GABABRs) can down-regulate most excitatory synapses in the CNS by reducing postsynaptic excitability. Functional GABABRs are heterodimers of GABAB1 and GABAB2 subunits and here we show that the trafficking and surface expression of GABABRs is differentially regulated by synaptic or pathophysiological activation of NMDA receptors (NMDARs). Activation of synaptic NMDARs using a chemLTP protocol increases GABABR recycling and surface expression. In contrast, excitotoxic global activation of synaptic and extrasynaptic NMDARs by bath application of NMDA causes the loss of surface GABABRs. Intriguingly, exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) increases GABAB1 but decreases GABAB2 surface expression. The increase in surface GABAB1 involves enhanced recycling and is blocked by the NMDAR antagonist AP5. The decrease in surface GABAB2 is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is critical in GABABR trafficking and function and that the individual subunits can be separately controlled to regulate neuronal responsiveness and survival.
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom. Electronic address: s.kantamneni@bradford.ac.uk.
authors.forename: Sriharsha
authors.initials: S
authors.lastname: Kantamneni
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Immaculada M
authors.initials: IM
authors.lastname: Gonzàlez-Gonzàlez
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Helena
authors.initials: H
authors.lastname: Cimarosti
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Jacobs
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Nadia
authors.initials: N
authors.lastname: Jaafari
authors.affiliation: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol BS8 1TD, United Kingdom. Electronic address: J.M.Henley@bristol.ac.uk.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Henley
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D009474:Neurons / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D018080:Receptors, GABA-B / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D013569:Synapses / Q000378:metabolism*
chemical_list: C116566:Gabbr2 protein, rat; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Chem-LTP; G Protein-coupled Receptors (GPCR); GABA Receptors; GABAB Receptor; Glutamate Receptor Ionotropic (AMPA, NMDA); Neurodegeneration; Neurotransmitter Receptors; Oxygen-glucose Deprivation (OGD); Receptor Endocytosis; Receptor Recycling