grin2b-protein

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

• 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

• 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]:

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]

• 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

• 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]

• 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

• 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

• 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

• 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

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

• 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

Cross-Linking Relationships

Related Proteins

• [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

Related Pathways

• [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

See Also

• [GRIN2B Gene](/genes/grin2b)
• [GRIN1 Protein](/proteins/grin1-protein)
• [NMDA Receptor Overview](/entities/nmda-receptor)
• [Excitotoxicity Mechanism](/mechanisms/excitotoxicity)
• [Alzheimer's Disease Mechanisms](/mechanisms/alzheimers-pathogenesis)
• [Parkinson's Disease Mechanisms](/mechanisms/parkinsons-pathogenesis)
• [Memantine Treatment](/treatments/memantine)

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