Platelet-derived Growth Factor Selectively Inhibits NR2B-containing N-Methyl-D-aspartate Receptors in CA1 Hippocampal Neurons

• Published in: The Journal of biological chemistry Vol. 284; no. 12; pp. 8054 - 8063
• Main Authors: Beazely, Michael A., Lim, Aeni, Li, Hongbin, Trepanier, Catherine, Chen, XuanMao, Sidhu, Bikram, MacDonald, John F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-03-2009; American Society for Biochemistry and Molecular Biology
• Subjects: Actins - metabolism; Animals; Becaplermin; Calcium - metabolism; Cyclic AMP Response Element-Binding Protein; Cytoskeleton - metabolism; Hippocampus - cytology; Hippocampus - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; N-Methylaspartate - metabolism; Neurons - cytology; Neurons - metabolism; Phenols - pharmacology; Phospholipase C gamma - metabolism; Piperidines - pharmacology; Platelet-Derived Growth Factor - metabolism; Platelet-Derived Growth Factor - pharmacology; Protein Kinase C - metabolism; Proto-Oncogene Proteins c-sis; Rats; Rats, Wistar; Receptor, Platelet-Derived Growth Factor beta - agonists; Receptor, Platelet-Derived Growth Factor beta - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Signal Transduction - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M805384200

Platelet-derived growth factor (PDGF) β receptor activation inhibits N-methyl-d-aspartate (NMDA)-evoked currents in hippocampal and cortical neurons via the activation of phospholipase Cγ, PKC, the release of intracellular calcium, and a rearrangement of the actin cytoskeleton. In the hippocampus, the majority of NMDA receptors are heteromeric; most are composed of 2 NR1 subunits and 2 NR2A or 2 NR2B subunits. Using NR2B- and NR2A-specific antagonists, we demonstrate that PDGF-BB treatment preferentially inhibits NR2B-containing NMDA receptor currents in CA1 hippocampal neurons and enhances long-term depression in an NR2B subunit-dependent manner. Furthermore, treatment of hippocampal slices or cultures with PDGF-BB decreases the surface localization of NR2B but not of NR2A subunits. PDGFβ receptors colocalize to a higher degree with NR2B subunits than with NR2A subunits. After neuronal injury, PDGFβ receptors and PDGF-BB are up-regulated and PDGFβ receptor activation is neuroprotective against glutamate-induced neuronal damage in cultured neurons. We demonstrate that the neuroprotective effects of PDGF-BB are occluded by the NR2B antagonist, Ro25-6981, and that PDGF-BB promotes NMDA signaling to CREB and ERK1/2. We conclude that PDGFβR signaling, by preferentially targeting NR2B receptors, provides an important mechanism for neuroprotection by growth factors in the central nervous system.