NMDA Receptor Subunit NR1 (GRIN1)

NMDA Receptor Subunit NR1 (GRIN1)

<div class="infobox">
<h3>NMDA Receptor Subunit NR1</h3>
<table>
<tr><td><strong>UniProt ID</strong></td><td>[P35439](https://www.uniprot.org/uniprot/P35439)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>105 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, 6MMP, 7EU7</td></tr>
<tr><td><strong>Gene</strong></td><td>[GRIN1](/entities/grin1)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

[NMDA receptor](/entities/nmda-receptor) NR1 subunit, essential glutamate-gated ion channel, obligatory subunit for all NMDA receptors.

Normal Function

The NMDA receptor subunit NR1 (GRIN1 gene product) is the obligatory subunit of all functional NMDA receptors. NR1 combines with NR2 (GRIN2A-D) and/or NR3 (GRIN3A-B) subunits to form heterotetrameric glutamate-gated ion channels. Key features include:

Structure

• Consists of an N-terminal domain (NTD), ligand-binding domain (LBD), transmembrane domain (TMD) forming the ion channel pore, and intracellular C-terminal domain (CTD)
• Contains the glycine/D-serine co-agonist binding site (unlike NR2 which binds glutamate)
• Eight splice variants generated from alternative splicing of exons 5, 21, and 22

NMDA Receptor Subunit NR1 (GRIN1)

<div class="infobox">
<h3>NMDA Receptor Subunit NR1</h3>
<table>
<tr><td><strong>UniProt ID</strong></td><td>[P35439](https://www.uniprot.org/uniprot/P35439)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>105 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, 6MMP, 7EU7</td></tr>
<tr><td><strong>Gene</strong></td><td>[GRIN1](/entities/grin1)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

[NMDA receptor](/entities/nmda-receptor) NR1 subunit, essential glutamate-gated ion channel, obligatory subunit for all NMDA receptors.

Normal Function

The NMDA receptor subunit NR1 (GRIN1 gene product) is the obligatory subunit of all functional NMDA receptors. NR1 combines with NR2 (GRIN2A-D) and/or NR3 (GRIN3A-B) subunits to form heterotetrameric glutamate-gated ion channels. Key features include:

Structure

• Consists of an N-terminal domain (NTD), ligand-binding domain (LBD), transmembrane domain (TMD) forming the ion channel pore, and intracellular C-terminal domain (CTD)
• Contains the glycine/D-serine co-agonist binding site (unlike NR2 which binds glutamate)
• Eight splice variants generated from alternative splicing of exons 5, 21, and 22

• Mediates excitatory neurotransmission crucial for synaptic plasticity
• Required for [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and long-term depression (LTD)
• High calcium permeability distinguishes NMDA receptors from AMPA receptors
• Voltage-dependent Mg²⁺ block allows coincidence detection (Hebbian plasticity)

• Critical for neuronal development, migration, and circuit formation
• Regulates dendritic spine morphology and synaptic maturation[@traynelis2010]

Role in Neurodegeneration

NMDA receptor dysfunction, particularly involving NR1, contributes to neurodegeneration through multiple mechanisms:

Excitotoxicity

• Excessive glutamate release leads to overactivation of NMDA receptors
• Massive calcium influx triggers downstream cell death pathways
• NR1-containing receptors are particularly vulnerable due to high calcium permeability
• Chronic excitotoxicity implicated in AD, PD, HD, ALS, and stroke[@lai2014]

• [Aβ](/proteins/amyloid-beta) oligomers potentiate NMDA receptor currents, increasing calcium influx
• NR1 phosphorylation by Fyn kinase enhances excitotoxic vulnerability
• Synaptic NMDA receptor loss precedes neuronal death
• Memantine (NMDA antagonist) approved for moderate-to-severe AD[@parsons2013]

• Striatal NMDA receptor dysregulation contributes to motor symptoms
• L-DOPA-induced dyskinesia involves NR1/NR2B upregulation
• NMDA antagonists showed efficacy in reducing dyskinesias[@chase1996]

• Acute excitotoxicity within minutes of ischemia onset
• NR1-containing receptors mediate the calcium overload
• Therapeutic window for NMDA antagonists limited by rapid cell death

• GRIN1 mutations cause developmental and epileptic encephalopathy
• Both gain-of-function and loss-of-function variants identified
• Some variants amenable to memantine treatment[@lemke2016]

Therapeutic Targeting

NMDA receptor targeting strategies in neurodegeneration:

Approved Therapies

• Memantine: Low-affinity uncompetitive NMDA antagonist; approved for moderate-to-severe AD; blocks excessive activation while preserving physiological signaling
• Amantadine: NMDA antagonist with additional mechanisms; used for PD dyskinesia

• GluN2B-selective antagonists: Target NR2B-containing receptors (more associated with excitotoxicity); ifenprodil derivatives
• Glycine site modulators: Target the NR1 glycine binding site
• Allosteric modulators: Preserve physiological function while reducing excitotoxicity
• Subunit-selective targeting: NR2B vs NR2A selectivity for differential effects[@wang2020]

• Narrow therapeutic window between neuroprotection and impairment
• Physiological NMDA receptor function essential for cognition
• Side effects: dissociative symptoms, memory impairment
• Timing critical (neuroprotection vs. recovery phases)

See Also

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

External Links

• [UniProt: P35439](https://www.uniprot.org/uniprot/P35439)
• [PDB structures](https://www.rcsb.org/search?q=uniprot:P35439)

References