Projects per year
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.
- G Protein-coupled Receptors (GPCR)
- GABA Receptors
- Glutamate Receptor Ionotropic (AMPA
- Neurotransmitter Receptors
- Receptor Endocytosis
- Receptor Recycling
- GABAB Receptor
- Oxygen-glucose Deprivation (OGD)
- LONG-TERM POTENTIATION
- LYSOSOMAL DEGRADATION
- RAT HIPPOCAMPUS
- AMPA RECEPTORS
- SLICE CULTURES
FingerprintDive into the research topics of 'Differential Regulation of GABA(B) Receptor Trafficking by Different Modes of N-methyl-D-aspartate (NMDA) Receptor Signaling'. Together they form a unique fingerprint.
- 3 Finished
Mechanisms and consequences of presynaptic protein SUMOylation in the regulation of neurotransmitter release
31/12/13 → 29/04/17
PROTEIN INTERACTIONS AND POST TRANSATIONAL MODIFICATION IN THE TRAFFICKING OF NEURONAL KAINATE RECEPTORS
1/01/08 → 1/10/11
1/01/08 → 1/01/13