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Platelet-derived growth factor selectively inhibits NR2B-containing N-methyl-D-aspartate receptors in CA1 hippocampal neurons.

ABSTRACT: 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.

SUBMITTER: Beazely MA

PROVIDER: S-EPMC2658099 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:N-Methyl-d-aspartate (NMDA)-type glutamate receptors mediate excitatory synaptic transmission in the central nervous system and play critical roles in many neuronal processes. The physiologic roles of NMDA receptors are shaped by their functional properties, which are highly dependent on subunit composition. Most NMDA receptors are assembled from two GluN1 and two GluN2 subunits, but diversity in subunit composition is made possible by eight GluN1 splice variants (i.e., isoforms) and four distinct GluN2 subunits (GluN2A-D). We demonstrate using Förster resonance energy transfer and fluorescence lifetime imaging that GluN1-1a and GluN1-1b isoforms, which include or lack residues encoded by exon 5, form triheteromeric GluN1-1a/GluN1-1b/GluN2A (1a/1b/2A) and GluN1-1a/GluN1-1b/GluN2B (1a/1b/2B) receptors. We describe the selective expression of NMDA receptors containing two different GluN1 isoforms, and show that triheteromeric 1a/1b/2A and 1a/1b/2B receptors exhibit intermediate deactivation kinetics and pharmacological properties compared with the respective diheteromeric GluN1-1a/GluN1-1a/GluN2 and GluN1-1b/GluN1-1b/GluN2 receptors. These results highlight the intriguing possibility that neurons can finely tune NMDA receptor signaling by shifting the ratio of expressed GluN1-1a and GluN1-1b isoforms. Furthermore, we evaluate the contribution of channel pore residues to magnesium block and calcium permeability. These data point to the asymmetric contribution of pore residues in GluN1 and GluN2 to magnesium block, and reveal that a single copy of pore residues from GluN3 subunits strongly attenuates magnesium block and calcium permeability of NMDA receptors. Thus, the selective expression of NMDA receptors containing two distinct GluN1 isoforms provides new opportunities to study functional properties relevant to neuronal receptors.

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