NMDA receptor-dependent GABA(B) receptor internalization via CaMKII phosphorylation of serine 867 in GABA(B1)

Guetg, Nicole and Aziz, Said Abdel and Holbro, Niklaus and Turecek, Rostislav and Rose, Tobias and Seddik, Riad and Gassmann, Martin and Moes, Suzette and Jenoe, Paul and Oertner, Thomas G. and Casanova, Emilio and Bettler, Bernhard. (2010) NMDA receptor-dependent GABA(B) receptor internalization via CaMKII phosphorylation of serine 867 in GABA(B1). Proceedings of the National Academy of Sciences (PNAS), 107 (31). pp. 13924-13929.

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Official URL: https://edoc.unibas.ch/63528/

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GABAB receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GABAB receptors are abundant on dendritic spines, where they dampen postsynaptic excitability and inhibit Ca2+ influx through NMDA receptors when activated by spillover of GABA from neighboring GABAergic terminals. Here, we show that an excitatory signaling cascade enables spines to counteract this GABAB-mediated inhibition. We found that NMDA application to cultured hippocampal neurons promotes dynamin-dependent endocytosis of GABAB receptors. NMDA-dependent internalization of GABAB receptors requires activation of Ca2+/Calmodulin-dependent protein kinase II (CaMKII), which associates with GABAB receptors in vivo and phosphorylates serine 867 (S867) in the intracellular C terminus of the GABAB1 subunit. Blockade of either CaMKII or phosphorylation of S867 renders GABAB receptors refractory to NMDA-mediated internalization. Time-lapse two-photon imaging of organotypic hippocampal slices reveals that activation of NMDA receptors removes GABAB receptors within minutes from the surface of dendritic spines and shafts. NMDA-dependent S867 phosphorylation and internalization is predominantly detectable with the GABAB1b subunit isoform, which is the isoform that clusters with inhibitory effector K+ channels in the spines. Consistent with this, NMDA receptor activation in neurons impairs the ability of GABAB receptors to activate K+ channels. Thus, our data support that NMDA receptor activity endocytoses postsynaptic GABAB receptors through CaMKII-mediated phosphorylation of S867. This provides a means to spare NMDA receptors at individual glutamatergic synapses from reciprocal inhibition through GABAB receptors.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Mass Spectrometry (Jenö)
03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Molecular Neurobiology Synaptic Plasticity (Bettler)
UniBasel Contributors:Jenö, Paul and Moes, Suzanne and Bettler, Bernhard
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:26 Oct 2023 15:40
Deposited On:09 Sep 2020 10:59

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