Platelet-derived growth factor selectively inhibits NR2B-containing N-methyl-D-aspartate receptors in CA1 hippocampal neurons.
Platelet-derived growth factor (PDGF) beta receptor activation inhibits N-methyl-d-aspartate (NMDA)-evoked currents in hippocampal and cortical neurons via the activation of phospholipase Cgamma, 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. PDGFbeta receptors colocalize to a higher degree with NR2B subunits than with NR2A subunits. After neuronal injury, PDGFbeta receptors and PDGF-BB are up-regulated and PDGFbeta 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 PDGFbetaR signaling, by preferentially targeting NR2B receptors, provides an important mechanism for neuroprotection by growth factors in the central nervous system.
Beazely
Michael A
MA
Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Lim
Aeni
A
Li
Hongbin
H
Trepanier
Catherine
C
Chen
Xuanmao
X
Sidhu
Bikram
B
Macdonald
John F
JF
D000199:Actins / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D002118:Calcium / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein; D003599:Cytoskeleton / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016202:N-Methylaspartate / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology; D051966:Phospholipase C gamma / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017208:Rats, Wistar; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000819:agonists / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000199:Actins; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D000077214:Becaplermin; D016202:N-Methylaspartate; D020797:Receptor, Platelet-Derived Growth Factor beta; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051966:Phospholipase C gamma; D002118:Calcium