NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1

Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13924-9. doi: 10.1073/pnas.1000909107. Epub 2010 Jul 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / chemistry
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Cells, Cultured
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Rats
  • Receptors, GABA-B / deficiency
  • Receptors, GABA-B / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Serine / genetics
  • Serine / metabolism

Substances

  • Receptors, GABA-B
  • Receptors, N-Methyl-D-Aspartate
  • Serine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2