Guetg, Nicole, Aziz, Said Abdel, Holbro, Niklaus, Turecek, Rostislav, Rose, Tobias, Seddik, Riad, Gassmann, Martin, Moes, Suzette, Jenoe, Paul, Oertner, Thomas, Casanova, Emilio and Bettler, Bernhard (2010) NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1. Proceedings of the National Academy of Sciences of the United States of America, 107 (31). pp. 13924-13929. ISSN 1091-6490

Abstract

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.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez...
Additional Information:	author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords:	γ-aminobutyric acid; spines; trafficking; synaptic plasticity, GABAB
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez...
Date Deposited:	04 Dec 2010 00:45
Last Modified:	01 Feb 2013 00:48
URI:	https://oak.novartis.com/id/eprint/3913