grin2b-protein

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GRIN2B Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">grin2b-protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Glutamate Ionotropic Receptor NMDA Type Subunit 2B (GluN2B/NR2B)</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GRIN2B</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q8VHX6](https://www.uniprot.org/uniprot/Q8VHX6) (mouse, ortholog)</td>
</tr>
<tr>
<td class="label">Human UniProt</td>
<td>[Q13224](https://www.uniprot.org/uniprot/Q13224)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~180 kDa (full-length); C-terminal tail ~70 kDa</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>1,484 amino acids</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>12p13.1</td>
</tr>
<tr>
<td class="label">Subcellular Location</td>
<td>Postsynaptic membrane, endoplasmic reticulum, Golgi</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Ionotropic glutamate receptor (iGluR) family</td>
</tr>
<tr>
<td class="label">Condition</td>
<td>Mutation Type</td>
</tr>
<tr>
<td class="label">Intellectual disability</td>
<td>Missense, nonsense</td>
</tr>
<tr>
<td class="label">Autism spectrum disorder</td>
<td>Missense</td>
</tr>
<tr>
<td class="label">Schizophrenia</td>
<td>Rare variants</td>
</tr>
<tr>
<td class="label">Epilepsy</td>
<td>Missense</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Mec

...

GRIN2B Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">grin2b-protein</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Glutamate Ionotropic Receptor NMDA Type Subunit 2B (GluN2B/NR2B)</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>GRIN2B</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[Q8VHX6](https://www.uniprot.org/uniprot/Q8VHX6) (mouse, ortholog)</td>
</tr>
<tr>
<td class="label">Human UniProt</td>
<td>[Q13224](https://www.uniprot.org/uniprot/Q13224)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~180 kDa (full-length); C-terminal tail ~70 kDa</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>1,484 amino acids</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>12p13.1</td>
</tr>
<tr>
<td class="label">Subcellular Location</td>
<td>Postsynaptic membrane, endoplasmic reticulum, Golgi</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Ionotropic glutamate receptor (iGluR) family</td>
</tr>
<tr>
<td class="label">Condition</td>
<td>Mutation Type</td>
</tr>
<tr>
<td class="label">Intellectual disability</td>
<td>Missense, nonsense</td>
</tr>
<tr>
<td class="label">Autism spectrum disorder</td>
<td>Missense</td>
</tr>
<tr>
<td class="label">Schizophrenia</td>
<td>Rare variants</td>
</tr>
<tr>
<td class="label">Epilepsy</td>
<td>Missense</td>
</tr>
<tr>
<td class="label">Drug</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">Memantine</td>
<td>Low-affinity, uncompetitive NMDAR antagonist</td>
</tr>
<tr>
<td class="label">Amantadine</td>
<td>NMDAR antagonist + dopamine release</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/bipolar" style="color:#ef9a9a">BIPOLAR</a>, <a href="/wiki/bipolar" style="color:#ef9a9a">Bipolar</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">72 edges</a></td>
</tr>
</table>

Overview

GRIN2B encodes the GluN2B (also called NR2B) subunit of the N-methyl-D-aspartate (NMDA) type of ionotropic glutamate receptor[@paoletti2013]. NMDA receptors are glutamate-gated, voltage-dependent calcium channels essential for synaptic transmission, synaptic plasticity, and activity-dependent gene expression. The GluN2B subunit confers distinctive physiological properties — including prolonged channel open time, high calcium permeability, and specific trafficking patterns — that are critical for hippocampal-dependent learning and memory, and whose dysregulation is implicated across Alzheimer's disease, Parkinson's disease, stroke, and neurodevelopmental disorders[@loftis2003].

The GluN2B subunit is encoded by [GRIN2B](/genes/grin2b) on chromosome 12p13.1. During brain development, GluN2B is widely expressed, but its expression becomes progressively restricted to forebrain regions (particularly the hippocampus and cortex) in the adult brain, with expression declining further with age — a pattern with significant implications for age-related cognitive decline[@Cull-Candy2001].

Protein Information

Structure

Domain Architecture

The GluN2B subunit adopts the canonical iGluR topology[@paoletti2013]:

Extracellular Domain (~570 residues):

ATD (Amino-Terminal Domain): Controls subunit assembly, controls agonist potency, mediates allosteric modulation by ifenprodil and related compounds
LBD (Ligand-Binding Domain): Bilobed structure binding glutamate (primary agonist) and glycine (co-agonist). The LBD undergoes domain closure upon agonist binding, driving channel opening

Transmembrane Domain:

Four transmembrane helices (M1–M4)
M2 forms the pore loop with a selectivity filter determining calcium permeability
The re-entrant M2 loop determines single-channel conductance

C-Terminal Domain (~640 residues):

Intracellular region bearing multiple serine, threonine, and tyrosine phosphorylation sites
Contains PDZ-binding motif for interaction with PSD-95, SAP97, and other MAGUK proteins
Critical for synaptic targeting, trafficking, and protein-protein interactions
Heavily regulated by kinases (CaMKII, PKC, Src family) and phosphatases

Assembly and Stoichiometry

Native NMDA receptors are obligate heteromers:

Diheteromeric: 2 GluN1 + 2 GluN2 (any subtype)
Triheteromeric: 2 GluN1 + 1 GluN2A + 1 GluN2B
GluN1 is the essential subunit (GRIN1 gene); GluN2B cannot form functional channels alone

Normal Function

Synaptic Physiology

GluN2B-containing NMDA receptors mediate several critical processes[@laurence2008]:

Calcium influx: High calcium permeability (PCa/PNa ~10) drives intracellular signaling cascades

Synaptic plasticity: Mediates long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus

Synaptic tagging: Couples synaptic activity to gene transcription for memory consolidation

Critical period plasticity: Enhanced during early postnatal development when environmental experience shapes neural circuits

Key Signaling Cascades

Downstream of GluN2B activation:

CaMKII activation: Autophosphorylation at T286, stabilizing synaptic potentiation
CREB phosphorylation: Activity-dependent gene expression (Bdnf, Arc, c-fos)
ERK/MAPK pathway: Synaptic protein synthesis and consolidation
Calcineurin/NFAT signaling: Bidirectional synaptic modulation

Regional and Temporal Expression

Developmental: Ubiquitously expressed across the CNS during fetal and early postnatal development
Adult: Enriched in hippocampus, cortex, striatum, and thalamus
Age-related decline: GluN2B expression at synapses decreases with normal aging, contributing to cognitive decline
Synaptic vs. extrasynaptic: Predominantly synaptic in mature neurons; extrasynaptic GluN2B-NMDARs trigger distinct (often pro-death) signaling

Role in Neurodegeneration

Alzheimer's Disease

GluN2B dysregulation is a hallmark of early AD pathogenesis[@liu2007]:

Excitotoxicity and calcium dysregulation:

Aβ oligomers activate GluN2B-containing NMDARs, causing pathological calcium influx
Excessive calcium influx activates calpains, caspases, and other proteases
Mitochondrial calcium overload leads to ROS generation and bioenergetic failure[@tu2014]

Synaptic damage:

Aβ-induced overactivation of synaptic NMDARs triggers internalization of AMPARs and NMDARs
Synaptic GluN2B loss precedes and predicts cognitive decline in animal models
Disruption of CaMKII signaling at synapses impairs LTP

Extrasynaptic GluN2B:

Aβ promotes translocation of GluN2B to extrasynaptic sites
Extrasynaptic GluN2B-NMDARs activate distinct signaling (pro-death pathways including PDE4, PP1)
Extrasynaptic NMDAR blockade is neuroprotective in AD models[@hardingham2007]

Therapeutic approaches:

Memantine: Low-affinity, uncompetitive NMDAR antagonist approved for moderate AD; preferentially blocks extrasynaptic NMDARs at therapeutic concentrations
NR2B-selective antagonists: Ifenprodil and analogs show promise in preclinical models
Allosteric modulators: Negative allosteric modulators targeting the ifenprodil binding site

Parkinson's Disease

NMDARs — particularly GluN2B-containing receptors — play key roles in PD pathophysiology[@kalia2008]:

Dopaminergic pathway dysregulation:

Loss of substantia nigra dopaminergic neurons disrupts striatal NMDAR regulation
Striatal GluN2B expression is altered in PD models and patients
Enhanced NMDAR signaling contributes to aberrant corticostriatal plasticity

L-DOPA-induced dyskinesia (LID):

Chronic L-DOPA treatment produces excessive NMDAR activity in striatal neurons
GluN2B upregulation is associated with LID severity
NR2B-selective antagonists (e.g., ifenprodil) reduce dyskinesia in animal models without diminishing antiparkinsonian efficacy

Neuroprotection:

NMDAR antagonists are neuroprotective in toxin-based PD models
Memantine has been explored as an adjunct to dopaminergic therapy

Stroke and Ischemia

Cerebral ischemia triggers massive glutamate release, leading to excitotoxic neuronal death[@kalia2008]:

Mechanism:

Oxygen-glucose deprivation causes energy failure, removing the voltage-dependent Mg²⁺ block on NMDARs
Excessive glutamate activates NMDARs including GluN2B-containing receptors
Massive Ca²⁺ influx triggers necrotic and apoptotic cascades

Therapeutic challenge:

Global NMDAR blockade is neuroprotective but causes unacceptable psychotomimetic side effects
NR2B-selective antagonists are more promising — neuroprotective in ischemia models with better safety margins
Timing is critical: NMDAR antagonists are most effective when administered before or shortly after ischemic insult

Neurodevelopmental Disorders

GRIN2B mutations cause a spectrum of neurodevelopmental conditions[@chang2022]:

Gain-of-function mutations (increased current, enhanced Ca²⁺ influx) cause severe early-onset encephalopathy with infantile spasms and developmental regression. Loss-of-function mutations produce intellectual disability with speech delay and dysmorphic features.

Therapeutic Approaches

Approved Therapies

Investigational Approaches

NR2B-selective antagonists:

Ifenprodil and analogs (e.g., CP-101,606/Trax配) — demonstrated neuroprotection in stroke, PD, and AD models
Challenge: selectivity is relative, not absolute — off-target effects on other targets

Allosteric modulators:

Rapastinel-like agents: Positive allosteric modulators (PAMs) targeting synaptic GluN2B-NMDARs for cognition enhancement
Negative allosteric modulators (NAMs) for excitotoxicity

Downstream targets:

CaMKII modulators: Enhance synaptic plasticity without broad NMDAR blockade
CREB enhancers: Bdnf-boosting strategies

Clinical Status

Memantine: Approved and widely used
NR2B antagonists: Multiple trials in AD, PD, and stroke — mixed results; no approved NR2B-selective drug
Prevention trials: Targeting early NMDAR dysfunction before neurodegeneration

Mechanism of Action

Mermaid diagram (expand to render)

Cross-Linking Relationships

[GRIN1](/proteins/grin1-protein) — Essential partner subunit forming functional NMDARs
[GRIN2A](/proteins/grin2a-protein) — Alternate GluN2 subunit with distinct properties
[PSD-95](/proteins/psd95-protein) — Scaffolding protein linking GluN2B to downstream signaling
[CaMKII](/proteins/camkii-protein) — Key downstream effector
[AMPAR](/proteins/ampa-receptor) — Synaptic co-receptor for rapid glutamatergic transmission

[Glutamatergic Synaptic Transmission](/mechanisms/glutamatergic-signaling) — Primary pathway
[Excitotoxicity](/mechanisms/excitotoxicity) — Pathological overactivation
[Long-Term Potentiation](/mechanisms/long-term-potentiation) — Synaptic plasticity
[Calcium Signaling](/mechanisms/calcium-signaling-neurons) — Downstream cascade
[Synaptic Plasticity](/mechanisms/synaptic-plasticity) — Learning and memory

Disease Associations

[Alzheimer's Disease](/diseases/alzheimers-disease) — Excitotoxicity, synaptic loss
[Parkinson's Disease](/diseases/parkinsons-disease) — Striatal dysregulation, LID
[Stroke](/diseases/stroke) — Ischemic excitotoxicity
[Intellectual Disability](/diseases/intellectual-disability) — GRIN2B mutations
[Epilepsy](/diseases/epilepsy) — GRIN2B mutations

External Links

[UniProt: Q13224](https://www.uniprot.org/uniprot/Q13224)
[NCBI Gene: GRIN2B](https://www.ncbi.nlm.nih.gov/gene/2904)
[GeneCards: GRIN2B](https://www.genecards.org/cgi-bin/carddisp.pl?gene=GRIN2B)
[IUPHAR: NMDAR subunits](https://www.guidetopharmacology.org/FL9/)
[Human Protein Atlas: GRIN2B](https://www.proteinatlas.org/ENSG00000116297-GRIN2B)

References

[Paoletti P, et al, NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23770197/)

[Loftis JM, et al, N-methyl-D-aspartate receptor subunit NR2B: molecular features and therapeutic implications (2003)](https://pubmed.ncbi.nlm.nih.gov/12669693/)

[Liu J, et al, Role of NMDA receptor subtypes in the pathogenesis of Alzheimer's disease (2007)](https://pubmed.ncbi.nlm.nih.gov/17904571/)

[Cull-Candy SG, et al, NMDA receptor subunits: diversity, development and disease (2001)](https://pubmed.ncbi.nlm.nih.gov/11301254/)

[Chen LJ, et al, NR2B transgenic mice: from enhanced cognition to neurodegeneration (2008)](https://pubmed.ncbi.nlm.nih.gov/17988788/)

[Kalia LV, et al, NMDA receptors in the pathophysiology and treatment of Parkinson's disease (2008)](https://pubmed.ncbi.nlm.nih.gov/18583679/)

[Lau CG, et al, Role of NMDA receptor trafficking in synaptic plasticity and disease (2009)](https://pubmed.ncbi.nlm.nih.gov/19333605/)

[Hardingham GE, et al, Extrasynaptic NMDARs oppose synaptic NMDARs by promoting cortical cell survival (2007)](https://pubmed.ncbi.nlm.nih.gov/17381548/)

[LaFerla FM, et al, Intracellular amyloid-beta in Alzheimer's disease (2007)](https://pubmed.ncbi.nlm.nih.gov/17950309/)

[Tu S, et al, Inflammatory neuronal death in Alzheimer's disease: Role of NMDA receptor overactivation (2014)](https://pubmed.ncbi.nlm.nih.gov/25131087/)

[Gardoni F, et al, Targeting NMDA receptor subunits as a strategy to treat Alzheimer's disease (2009)](https://pubmed.ncbi.nlm.nih.gov/19355845/)

[Chang CH, et al, GRIN2B variants in neurodevelopmental disorders: a systematic review (2022)](https://pubmed.ncbi.nlm.nih.gov/36080985/)

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Related Entities

GRIN2BPROTEIN

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-grin2b-protein
kg_node_id	GRIN2BPROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c0bc4edfe7ae
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-grin2b-protein'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

12

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

grin2b-protein

GRIN2B Protein

GRIN2B Protein

Overview

Protein Information

Structure

Domain Architecture

Assembly and Stoichiometry

Normal Function

Synaptic Physiology

Key Signaling Cascades

Regional and Temporal Expression

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Stroke and Ischemia

Neurodevelopmental Disorders

Therapeutic Approaches

Approved Therapies

Investigational Approaches

Clinical Status

Mechanism of Action

Cross-Linking Relationships

Disease Associations

See Also

External Links

References

💬 Discussion

📗 Cite This Artifact

grin2b-protein

GRIN2B Protein

GRIN2B Protein

Overview

Protein Information

Structure

Domain Architecture

Assembly and Stoichiometry

Normal Function

Synaptic Physiology

Key Signaling Cascades

Regional and Temporal Expression

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Stroke and Ischemia

Neurodevelopmental Disorders

Therapeutic Approaches

Approved Therapies

Investigational Approaches

Clinical Status

Mechanism of Action

Cross-Linking Relationships

Related Proteins

Related Pathways

Disease Associations

See Also

External Links

References

💬 Discussion