NMDA Receptor Subunit NR2B (GRIN2B)

NMDA Receptor Subunit NR2B (GRIN2B)

<div class="infobox">
<h3>NMDA Receptor Subunit NR2B</h3>
<table>
<tr><td><strong>UniProt ID</strong></td><td>[Q13224](https://www.uniprot.org/uniprot/Q13224)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>166 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Plasma membrane, postsynaptic density</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>4PE5, 5FXG, 6MMQ</td></tr>
<tr><td><strong>Gene</strong></td><td>[GRIN2B](/entities/grin2b)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">3 edges</a></td>
</tr>
</table>
</div>

Overview

[NMDA receptor](/entities/nmda-receptor) NR2B subunit, glutamate-binding modulatory subunit, regulates channel kinetics and synaptic localization.

Normal Function

The NMDA receptor subunit NR2B (GRIN2B gene product) is a modulatory subunit that combines with NR1 to form functional NMDA receptors. NR2B confers unique biophysical and pharmacological properties:

Structure and Assembly

• Large N-terminal domain with ifenprodil binding site (NR2B-selective antagonist)
• Glutamate-binding domain (distinct from NR1's glycine site)
• C-terminal domain with PDZ-binding motif for synaptic anchoring
• Forms heterotetramers: typically 2 NR1 + 2 NR2 subunits

NMDA Receptor Subunit NR2B (GRIN2B)

<div class="infobox">
<h3>NMDA Receptor Subunit NR2B</h3>
<table>
<tr><td><strong>UniProt ID</strong></td><td>[Q13224](https://www.uniprot.org/uniprot/Q13224)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>166 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Plasma membrane, postsynaptic density</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>4PE5, 5FXG, 6MMQ</td></tr>
<tr><td><strong>Gene</strong></td><td>[GRIN2B](/entities/grin2b)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">3 edges</a></td>
</tr>
</table>
</div>

Overview

[NMDA receptor](/entities/nmda-receptor) NR2B subunit, glutamate-binding modulatory subunit, regulates channel kinetics and synaptic localization.

Normal Function

The NMDA receptor subunit NR2B (GRIN2B gene product) is a modulatory subunit that combines with NR1 to form functional NMDA receptors. NR2B confers unique biophysical and pharmacological properties:

Structure and Assembly

• Large N-terminal domain with ifenprodil binding site (NR2B-selective antagonist)
• Glutamate-binding domain (distinct from NR1's glycine site)
• C-terminal domain with PDZ-binding motif for synaptic anchoring
• Forms heterotetramers: typically 2 NR1 + 2 NR2 subunits

• Predominantly expressed early in development
• Gradual switch from NR2B to NR2A during maturation (synaptic pruning)
• NR2B-rich receptors mediate developmental plasticity
• Adult expression concentrated in forebrain, [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex)[@monyer1992]

• Longer channel open time compared to NR2A-containing receptors
• Higher affinity for glutamate (prolonged activation)
• Enhanced calcium influx per activation event
• Slower deactivation kinetics

• Critical for spine development and synaptic maturation
• Mediates [long-term potentiation](/mechanisms/long-term-potentiation) in hippocampus
• PSD-95 interaction via C-terminus anchors receptors at synapses
• Activity-dependent trafficking regulates surface expression[@van2004]

Role in Neurodegeneration

NR2B-containing NMDA receptors are particularly implicated in excitotoxic neurodegeneration:

Excitotoxicity Vulnerability

• NR2B-rich receptors generate larger calcium loads than NR2A-containing receptors
• Extrasynaptic NR2B receptors particularly linked to cell death signaling
• Prolonged glutamate exposure preferentially activates NR2B receptors
• Distinct downstream signaling: NR2B → calpain, mitochondrial dysfunction, cell death[@liu2019]

• [Aβ](/proteins/amyloid-beta) oligomers increase surface expression of NR2B receptors
• Enhanced NR2B-dependent calcium influx contributes to synaptic loss
• NR2B-Fyn interaction promotes [tau](/proteins/tau) pathology
• NR2B antagonists show neuroprotection in AD models
• Memantine preferentially blocks overactive NR2B-containing receptors[@liu2009]

• Striatal NR2B upregulation observed in HD models
• Mutant [huntingtin](/proteins/huntingtin) enhances NR2B surface expression
• NR2B-selective antagonists reduce striatal degeneration
• Enhanced sensitivity to quinolinic acid excitotoxicity[@li2002]

• NR2B-containing receptors mediate hypoxic neuronal death
• Ifenprodil (NR2B antagonist) reduces infarct size in animal models
• Clinical trials limited by side effects and therapeutic window

• GRIN2B mutations cause epileptic encephalopathy
• Gain-of-function variants: increased seizure susceptibility
• Loss-of-function: intellectual disability, autism features
• Some variants respond to memantine or ketamine[@lemke2014]

Therapeutic Targeting

NR2B-selective targeting offers potential advantages in neurodegeneration:

NR2B-Selective Antagonists

• Ifenprodil: Prototypical NR2B antagonist; binds allosteric site on N-terminal domain
• Traxoprodil (CP-101,606): Investigated for stroke and depression
• EVT-101: Phase II trials for depression and neuropathic pain
• Radiprodil: Under investigation for developmental disorders with GRIN2B gain-of-function

• NR2B antagonists generally well-tolerated compared to non-selective NMDA antagonists
• Less impairment of synaptic plasticity than channel blockers
• Potential applications in HD, PD dyskinesia, stroke, depression
• Therapeutic window still narrow for acute neuroprotection[@yao2014]

• Activity-dependent blockers: Enhanced inhibition during sustained activation
• Bi-functional compounds: NR2B antagonist + additional neuroprotective mechanism
• Gene therapy: Antisense oligonucleotides targeting NR2B
• Combination therapy: NR2B antagonists + antioxidants or anti-inflammatory agents

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [UniProt: Q13224](https://www.uniprot.org/uniprot/Q13224)
• [PDB structures](https://www.rcsb.org/search?q=uniprot:Q13224)

References