NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1.
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NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1. / Guetg, Nicole; Said, Abdel Aziz; Holbro, Niklaus; Turecek, Rostislav; Rose, Tobias; Seddik, Riad; Gassmann, Martin; Moes, Suzette; Jenoe, Paul; Oertner, Thomas G.; Casanova, Emilio; Bettler, Bernhard.
in: P NATL ACAD SCI USA, Jahrgang 107, Nr. 31, 31, 2010, S. 13924-13929.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - NMDA receptor-dependent GABAB receptor internalization via CaMKII phosphorylation of serine 867 in GABAB1.
AU - Guetg, Nicole
AU - Said, Abdel Aziz
AU - Holbro, Niklaus
AU - Turecek, Rostislav
AU - Rose, Tobias
AU - Seddik, Riad
AU - Gassmann, Martin
AU - Moes, Suzette
AU - Jenoe, Paul
AU - Oertner, Thomas G.
AU - Casanova, Emilio
AU - Bettler, Bernhard
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Animals
KW - Cells, Cultured
KW - Mice
KW - Mice, Knockout
KW - Rats
KW - Amino Acid Sequence
KW - Phosphorylation
KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2/chemistry/metabolism
KW - Receptors, GABA-B/deficiency/metabolism
KW - Receptors, N-Methyl-D-Aspartate/metabolism
KW - Serine/genetics/metabolism
KW - Animals
KW - Cells, Cultured
KW - Mice
KW - Mice, Knockout
KW - Rats
KW - Amino Acid Sequence
KW - Phosphorylation
KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2/chemistry/metabolism
KW - Receptors, GABA-B/deficiency/metabolism
KW - Receptors, N-Methyl-D-Aspartate/metabolism
KW - Serine/genetics/metabolism
M3 - SCORING: Journal article
VL - 107
SP - 13924
EP - 13929
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 31
M1 - 31
ER -
