NMDA Receptor Subunit NR1 (GRIN1)

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NMDA Receptor Subunit NR1 (GRIN1)

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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

Synaptic Function

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)

Developmental Role

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]

Alzheimer's Disease

[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]

Parkinson's Disease

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

Stroke and Ischemia

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

Genetic Disorders

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

Investigational Approaches

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]

Challenges

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)

External Links

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

References

[Traynelis SF, et al, Glutamate receptor ion channels (2010)](https://doi.org/10.1002/pdt.19156)

[Lai TW, et al, Excitotoxicity and stroke: identifying specific targets for neuroprotection (2014)](https://doi.org/10.1155/2014/475289)

[Parsons CG, et al, Memantine: a NMDA receptor antagonist with neuroprotective properties (2013)](https://doi.org/10.1016/j.neuint.2013.11.007)

[Chase TN, et al, NMDA receptor antagonists for Parkinson's disease (1996)](https://doi.org/10.1002/mds.870111102)

[Lemke JR, et al, GRIN1 mutations in neurodevelopmental disorders (2016)](https://doi.org/10.1038/ejhg.2016.165)

[Wang LY, et al, NMDA receptor subunit-selective modulators for neurological disorders (2020)](https://doi.org/10.1016/j.neuron.2020.03.015)

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Related Entities

NMDAR1

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slug	proteins-nmdar1
kg_node_id	NMDAR1
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-210cee2e2f0a
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-nmdar1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

60%

Debates

0

Incoming

12

Outgoing

13

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

NMDA Receptor Subunit NR1 (GRIN1)

NMDA Receptor Subunit NR1 (GRIN1)

Overview

Normal Function

NMDA Receptor Subunit NR1 (GRIN1)

Overview

Normal Function

Role in Neurodegeneration

Therapeutic Targeting

See Also

External Links

References

💬 Discussion