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.
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
Digital Object Identifier (DOI)
Beazely MA, Lim A, Li H, Trepanier C, Chen X, Sidhu B, Macdonald JF. Platelet-derived growth factor selectively inhibits NR2B-containing N-methyl-D-aspartate receptors in CA1 hippocampal neurons. The Journal of biological chemistry. 2009;284(12):8054-63. doi: 10.1074/jbc.M805384200. PubMed PMID: 19106110; PubMed Central PMCID: PMC2658099
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc