The NMDA receptor (NMDAR) is a component of excitatory synapses and a key participant in synaptic plasticity. We investigated the role of two domains in the C terminus of the NR2B subunit--the PDZ binding domain and the clathrin adaptor protein (AP-2) binding motif--in the synaptic localization of NMDA receptors. NR2B subunits lacking functional PDZ binding are excluded from the synapse. Mutati...

Glutamate (Glu), a major excitatory neurotransmitter within the hypothalamus and thalamus, acts upon many receptors, including the N-methyl-D-aspartate (NMDA) subtype. Abundant evidence suggests that variations in the subunit composition of NMDA receptors (NMDA-Rs) contribute to differences in Glu's immediate electrophysiological effects as well as to the patterns of signal transduction cascade...

The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to the investigation of negative allosteric modulators (NAMs) selective for the NR2B receptor subtype. The clinical development of NR2B NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition of NR2B receptors in precl...

The neural changes that limit the sensitive period for avian song development are unknown, but neurons in a forebrain region critical for song learning, the lMAN, exhibit experience-driven changes in NMDAR subunit expression that could regulate sensitive period closure. Specifically, NR2B levels in lMAN decrease during song acquisition, potentially reducing synaptic plasticity by decreasing NMD...

Contextual fear conditioning is regulated by the hippocampus, and NR2B, a subunit of the NMDA receptor (NR), is involved in this process. We show that acute stress modulates tissue plasminogen activator (tPA) activity in the hippocampus by inducing expression of its inhibitor, plasminogen activator inhibitor-1. Acute stress increases NR2B expression and ERK1/2 phosphorylation, a classical marke...

Comparative Analyses of Rodent and Human Brain in Ageing and Disease using novel NMDAR-2B Selective Probes. The NMDA subtype of excitatory ionotropic glutamate receptors is a hetero-oligomeric ligand-gated ion channel. Molecular cloning techniques have identified three types of NMDA receptor subunits, the NR1, NR2A-D, and NR3A-B. NR2B-containing receptors are the focus of this thesis and are be...

The coupling of the spinal postsynaptic density-95 (PSD-95) with the glutamatergic N-methyl-d-aspartate receptor NR2B subunit and the subsequent NR2B phosphorylation contribute to pain-related plasticity. Increasing evidence reveals that kalirin, a Rho-guanine nucleotide exchange factor, modulates PSD-95-NR2B-dependent neuroplasticity. Our laboratory recently demonstrated that serum-inducible a...

A hallmark feature of N-methyl-D-aspartate (NMDA) receptors is their voltage-dependent block by extracellular Mg2+. The structural basis for Mg2+ block is not fully understood. Although asparagine residues in the pore-forming M2 regions of NR1 and NR2 subunits influence Mg2+ block, it has been speculated that additional residues are likely to be involved. Here, we report the unexpected finding ...

N-methyl-D-aspartate receptors (NMDARs) are known to regulate axonal refinement and dendritic branching. However, because NMDARs are abundantly present as tri-heteromers (e.g., NR1/NR2A/NR2B) during development, the precise role of the individual subunits NR2A and NR2B in these processes has not been elucidated. Ventral spinal cord neurons (VSCNs) provide a unique opportunity to address this pr...

Pain and learning memory have striking similarities in synaptic plasticity. Activation of the N-methyl-D-aspartic acid receptors 2B subunits (NR2B-NMDAs) is responsible for the hippocampal LTP in memory formation. In our previous studies, we found the significant enhancement of CA1 hippocampal long-term potentiation (LTP) induced by high-frequency stimulation (HFS) in rats with chronic visceral...