Cdk5 regulates the phosphorylation of tyrosine 1472 NR2B and the surface expression of NMDA receptors
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2008-01-11Keywords
Adaptor Protein Complex 2Analysis of Variance
Animals
Cells, Cultured
Cerebral Cortex
Cyclin-Dependent Kinase 5
Embryo, Mammalian
Enzyme Inhibitors
Female
Humans
Indoles
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Neurons
Phosphorylation
Pregnancy
Rats
Receptors, N-Methyl-D-Aspartate
SH2 Domain-Containing Protein Tyrosine Phosphatases
Sulfonamides
Synaptosomes
Transfection
Tyrosine
Cell Biology
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
NMDA receptors (NMDARs) are a major class of ionotropic glutamate receptors that can undergo activity-dependent changes in surface expression. Clathrin-mediated endocytosis is a mechanism by which the surface expression of NR2B-containing NMDA receptors is regulated. The C terminus of the NMDA receptor subunit NR2B contains the internalization motif YEKL, which is the binding site for the clathrin adaptor AP-2. The tyrosine (Y1472) within the YEKL motif is phosphorylated by the Src family of kinases and this phosphorylation inhibits the binding of AP-2 and promotes surface expression of NMDA receptors. Cdk5 is a serine/threonine kinase that has been implicated in synaptic plasticity, learning, and memory. Here we demonstrate that inhibition of Cdk5 results in increased phosphorylation of Y1472 NR2B at synapses and decreased binding of NR2B to beta2-adaptin, a subunit of AP-2, thus blocking the activity-dependent endocytosis of NMDA receptors. Furthermore, we show that inhibition of Cdk5 increases the binding of Src to postsynaptic density-95 (PSD-95), and that expression of PSD-95 facilitates the phosphorylation of Y1472 NR2B by Src. Together, these results suggest a model in which inhibition of Cdk5 increases the binding of Src to PSD-95 and the phosphorylation of Y1472 NR2B by Src, which results in decreased binding of NR2B to AP-2, and NR2B/NMDAR endocytosis. This study provides a novel molecular mechanism for the regulation of the surface expression of NR2B-containing NMDA receptors and gives insight into the Cdk5-dependent regulation of synaptic plasticity.Source
J Neurosci. 2008 Jan 9;28(2):415-24. Link to article on publisher's siteDOI
10.1523/JNEUROSCI.1900-07.2008Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39269PubMed ID
18184784Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1523/JNEUROSCI.1900-07.2008