Differential Regulation of GABA(B) Receptor Trafficking by Different Modes of N-methyl-D-aspartate (NMDA) Receptor Signaling

S Kantamneni, Maria Inmaculada Gonzalez, Jia Luo, Helena Cimarosti, Sue C Jacobs, Nadia Jaafari, Jeremy M. Henley

Research output: Contribution to journalArticle (Academic Journal)peer-review

15 Citations (Scopus)

Abstract

Background: Heterodimerization of GABA(B1) and GABA(B2) subunits is required for functional GABA(B)Rs. Results: GABA(B)R subunits are differentially regulated by activation of synaptic or extrasynaptic NMDARs. Conclusion: GABA(B)R trafficking and function is regulated by NMDARs. Significance: GABA(B)Rs are potential targets for treating diseases such as stroke and cerebral ischemia.

Inhibitory GABA(B) receptors (GABA(B)Rs) can down-regulate most excitatory synapses in the CNS by reducing postsynaptic excitability. Functional GABA(B)Rs are heterodimers of GABA(B1) and GABA(B2) subunits and here we show that the trafficking and surface expression of GABA(B)Rs is differentially regulated by synaptic or pathophysiological activation of NMDA receptors (NMDARs). Activation of synaptic NMDARs using a chemLTP protocol increases GABA(B)R recycling and surface expression. In contrast, excitotoxic global activation of synaptic and extrasynaptic NMDARs by bath application of NMDA causes the loss of surface GABA(B)Rs. Intriguingly, exposing neurons to extreme metabolic stress using oxygen/glucose deprivation (OGD) increases GABA(B1) but decreases GABA(B2) surface expression. The increase in surface GABA(B1) involves enhanced recycling and is blocked by the NMDAR antagonist AP5. The decrease in surface GABA(B2) is also blocked by AP5 and by inhibiting degradation pathways. These results indicate that NMDAR activity is critical in GABA(B)R trafficking and function and that the individual subunits can be separately controlled to regulate neuronal responsiveness and survival.

Original languageEnglish
Pages (from-to)6681-6694
Number of pages14
JournalJournal of Biological Chemistry
Volume289
Issue number10
DOIs
Publication statusPublished - 7 Mar 2014

Keywords

  • G Protein-coupled Receptors (GPCR)
  • GABA Receptors
  • Glutamate Receptor Ionotropic (AMPA
  • NMDA)
  • Neurodegeneration
  • Neurotransmitter Receptors
  • Receptor Endocytosis
  • Receptor Recycling
  • GABAB Receptor
  • Chem-LTP
  • Oxygen-glucose Deprivation (OGD)
  • GAMMA-AMINOBUTYRIC-ACID
  • LONG-TERM POTENTIATION
  • HIPPOCAMPAL-NEURONS
  • LYSOSOMAL DEGRADATION
  • RAT HIPPOCAMPUS
  • AMPA RECEPTORS
  • SLICE CULTURES
  • PROTEIN
  • SUBUNITS
  • ACTIVATION

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