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Phosphorylation of the kainate receptor (KAR) auxiliary subunit Neto2 at serine 409 regulates synaptic targeting of the KAR subunit GluK1.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2017 Sep 15; Vol. 292 (37), pp. 15369-15377. Date of Electronic Publication: 2017 Jul 17. - Publication Year :
- 2017
-
Abstract
- Synaptic strength at excitatory synapses is determined by the presence of glutamate receptors ( i.e. AMPA, NMDA, and kainate receptors) at the synapse. Synaptic strength is modulated by multiple factors including assembly of different receptor subunits, interaction with auxiliary subunits, and post-translational modifications of either the receptors or their auxiliary subunits. Using mass spectrometry, we found that the intracellular region of neuropilin and tolloid-like proteins (Neto) 1 and Neto2, the auxiliary subunits of kainate receptor (KARs), are phosphorylated by multiple kinases in vitro Specifically, Neto2 was phosphorylated at serine 409 (Ser-409) by Ca <superscript>2+</superscript> /calmodulin-dependent protein kinase II (CaMKII) and protein kinase A (PKA) both in vitro and in heterologous cells. Interestingly, we observed a substantial increase in Neto2 Ser-409 phosphorylation in the presence of CaMKII, and this phosphorylation was reduced in the presence of the KAR subunit GluK1 or GluK2. We also found endogenous phosphorylation of Neto2 at Ser-409 in the brain. Moreover, Neto2 Ser-409 phosphorylation inhibited synaptic targeting of GluK1 because, unlike WT Neto2 and the phosphodeficient mutant Neto2 S409A, the Neto2 S409D phosphomimetic mutant impeded GluK1 trafficking to synapses. These results support a molecular mechanism by which Neto2 phosphorylation at Ser-409 helps restrict GluK1 targeting to the synapse.
- Subjects :
- Amino Acid Substitution
Animals
Animals, Newborn
Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics
Cell Line, Transformed
Chlorocebus aethiops
Hippocampus cytology
Hippocampus metabolism
Humans
Membrane Proteins chemistry
Membrane Proteins genetics
Nerve Tissue Proteins chemistry
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Neurons cytology
Neurons enzymology
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
Phosphorylation
Point Mutation
Protein Interaction Domains and Motifs
Protein Transport
Rats
Receptors, Kainic Acid chemistry
Receptors, Kainic Acid genetics
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins metabolism
Serine metabolism
Tissue Culture Techniques
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits metabolism
Membrane Proteins metabolism
Neurons metabolism
Protein Processing, Post-Translational
Receptors, Kainic Acid metabolism
Synapses metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 292
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28717010
- Full Text :
- https://doi.org/10.1074/jbc.M117.787903