title: NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1.
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.
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Guetg
authors.forename: Said
authors.initials: S
authors.lastname: Abdel Aziz
authors.forename: Niklaus
authors.initials: N
authors.lastname: Holbro
authors.forename: Rostislav
authors.initials: R
authors.lastname: Turecek
authors.forename: Tobias
authors.initials: T
authors.lastname: Rose
authors.forename: Riad
authors.initials: R
authors.lastname: Seddik
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.forename: Suzette
authors.initials: S
authors.lastname: Moes
authors.forename: Paul
authors.initials: P
authors.lastname: Jenoe
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Oertner
authors.forename: Emilio
authors.initials: E
authors.lastname: Casanova
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051381:Rats; D018080:Receptors, GABA-B / Q000172:deficiency / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism
chemical_list: D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2