GRIA1 (Glutamate Ionotropic Receptor AMPA Type Subunit 1): Genetics, Expression, and Clinical Significance
A comprehensive biomedical overview of the GRIA1 gene, encoding the GluA1 AMPA receptor subunit, including its genomic context, expression patterns, associated diseases, and functional roles.
Gene Information Card
| Symbol | GRIA1 |
|---|---|
| Full Name | Glutamate Ionotropic Receptor AMPA Type Subunit 1 |
| Gene Type | protein coding |
| Chromosomal Location | 5q33.2 |
| NCBI Gene ID | 2890 ncbi.nlm.nih.gov/gene/2890 |
| Ensembl ID | ENSG00000155511 |
| UniProt ID | P42261 |
| OMIM ID | 138248 |
| HGNC ID | 4571 |
| Aliases | GluA1, GLUH1, GluR1, GLUR1, GLURA, HBGR1 |
Description
The GRIA1 gene encodes the glutamate ionotropic receptor AMPA type subunit 1 (GluA1), a core component of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. AMPA receptors are ligand-gated ion channels that mediate the majority of fast excitatory synaptic transmission in the central nervous system. The GluA1 subunit is critical for receptor assembly, trafficking, and channel function. It is widely expressed in the brain, particularly in the hippocampus, cortex, and basal ganglia. GRIA1 is involved in synaptic plasticity, learning, and memory. Mutations and dysregulation of GRIA1 have been implicated in various neurodevelopmental and neuropsychiatric disorders, including intellectual disability, autism spectrum disorder, and epilepsy.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Disease | Mechanism | Evidence |
| Intellectual Disability (ID) | Heterozygous missense and truncating variants in GRIA1 can lead to haploinsufficiency or dominant-negative effects, disrupting AMPA receptor function and synaptic transmission, which is critical for cognitive development. | ClinVar, OMIM (138248) |
| Autism Spectrum Disorder (ASD) | De novo and inherited variants in GRIA1 have been identified in individuals with ASD, suggesting a role in the disruption of glutamatergic signaling pathways that affect social behavior and communication. | ClinVar, NCBI |
| Epilepsy | Pathogenic variants in GRIA1 can alter channel gating or ion permeability, leading to neuronal hyperexcitability and increased susceptibility to seizures. | ClinVar, OMIM (138248) |
| Neurodevelopmental Disorder with Language Impairment and Behavioral Abnormalities (NEDLBA) | Specific missense mutations in GRIA1 are associated with this syndrome, characterized by developmental delay, speech and language deficits, and behavioral issues, likely due to altered receptor function. | OMIM (138248) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Tissue | nTPM | Level |
| Cerebral Cortex | ~250 | High |
| Hippocampus | ~200 | High |
| Cerebellum | ~150 | Medium |
| Basal Ganglia | ~120 | Medium |
| Spinal Cord | ~50 | Low |
| Testis | ~10 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Cell Line | nTPM | Notes |
| SH-SY5Y (Neuroblastoma) | ~80 | Neuronal-like cells; expression is used as a model for neuronal function. |
| U-87 MG (Glioblastoma) | ~30 | Expression in glial tumors may reflect aberrant signaling. |
| HepG2 (Hepatocellular Carcinoma) | ~1 | Very low expression; not a primary site of GRIA1 function. |
| A549 (Lung Carcinoma) | ~0.5 | Minimal expression; not a primary site of GRIA1 function. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| Variant | Type | Frequency | Effect |
| p.Arg546Gln (c.1637G>A) | Missense | Rare (found in ID/ASD cohorts) | Alters channel gating and reduces receptor function, likely contributing to neurodevelopmental phenotypes. |
| p.Gly830Arg (c.2488G>A) | Missense | Rare (de novo in NEDLBA) | Dominant-negative effect, impairing receptor trafficking and surface expression. |
| p.Arg450* (c.1348C>T) | Nonsense | Rare (de novo in ID) | Introduces a premature stop codon, leading to nonsense-mediated decay and haploinsufficiency. |
| c.1900+1G>T | Splice-site | Rare (reported in epilepsy) | Disrupts canonical splicing, likely leading to exon skipping and a non-functional protein. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations, including nonsense, frameshift, and some missense variants, reduce the number of functional GluA1 subunits. This leads to haploinsufficiency, where the single functional allele is insufficient to maintain normal AMPA receptor levels, impairing synaptic plasticity and cognitive function.
Gain of Function (GOF)
Gain-of-function mutations are less common but can occur. These variants may increase channel conductance, alter ion selectivity (e.g., increased calcium permeability), or prolong channel opening, leading to neuronal hyperexcitability and excitotoxicity, which is particularly relevant in epilepsy phenotypes.
Dominant Negative (DN)
Dominant-negative mutations, often missense variants in critical domains, produce a mutant protein that can oligomerize with wild-type subunits. This disrupts the assembly and trafficking of the entire receptor complex, effectively reducing the number of functional receptors at the synapse more severely than haploinsufficiency alone.
View complete mutation data：
Gene Ontology (GO)
| • ionotropic glutamate receptor activity | • AMPA glutamate receptor activity |
| • ligand-gated ion channel activity | • glutamate binding |
| • ion channel activity | • plasma membrane |
| • postsynaptic membrane | • synapse |
| • dendrite | • chemical synaptic transmission |
| • excitatory postsynaptic potential | • regulation of membrane potential |
| • learning or memory | • response to amphetamine |
Pathways
• Glutamatergic synapse
• Neuroactive ligand-receptor interaction
• Long-term potentiation (LTP)
• Long-term depression (LTD)
• Postsynaptic signal transduction
Protein Summary
The GluA1 protein (UniProt P42261) is a 906-amino-acid, multi-pass membrane protein that forms the pore of the AMPA receptor. It consists of a large extracellular N-terminal domain (ATD) involved in subunit assembly, a ligand-binding domain (LBD) that binds glutamate, three transmembrane domains (M1, M3, M4), and a re-entrant pore loop (M2) that determines ion selectivity. The intracellular C-terminal domain is crucial for protein-protein interactions, phosphorylation, and receptor trafficking. GluA1 can form homomeric or heteromeric receptors with other AMPA subunits (GluA2, GluA3, GluA4). The presence of the GluA2 subunit typically renders the receptor impermeable to calcium; however, GluA1 homomers are calcium-permeable. Post-translational modifications, such as phosphorylation at Ser831 and Ser845, regulate channel conductance and receptor surface expression, playing a key role in synaptic plasticity.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| GRIA1 Knockout HEK293 Cell Line | EDJ-KQ1815 | Human | 2890 | Details Get a Quote |
| GRIA1 Knockout HeLa Cell Line | EDJ-KQ53419 | Human | 2890 | Details Get a Quote |
| GRIA1 Knockout A-549 Cell Line | EDJ-KQ61895 | Human | 2890 | Details Get a Quote |
| GRIA1 Knockout HCT 116 Cell Line | EDJ-KQ70376 | Human | 2890 | Details Get a Quote |
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