Gabra5 — Gaba A Receptor Alpha 5 Subunit is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
GABRA5 (Gamma-Aminobutyric Acid Type A Receptor Alpha 5 Subunit) encodes the alpha-5 subunit of the GABA-A receptor, which is enriched in the hippocampus and plays important roles in memory and cognition.
| Attribute |
Value |
| Gene Symbol |
GABRA5 |
| Full Name |
GABA-A Receptor Alpha 5 Subunit |
| Chromosomal Location |
15q12 |
| NCBI Gene ID |
2568 |
| OMIM |
137142 |
| Ensembl ID |
ENSG00000118190 |
| UniProt |
P31644 |
The GABRA5 gene encodes the GABA-A receptor alpha-5 subunit, a 456 amino acid protein.
- UniProt ID: P31644
- Molecular Weight: ~52 kDa
- Subcellular Localization: Neuronal cell membrane, postsynaptic density
- Protein Family: Cys-loop receptor family, GABA-A receptor family
GABA-A α5 has characteristic Cys-loop receptor architecture:
¶ Extracellular Domain
- N-terminal domain: Ligand binding site
- Cys-loop motif: Characteristic disulfide bond
- Loop structures: 6 loops (A-F) form binding pocket
¶ Transmembrane Domain
- 4 transmembrane helices: M1-M4
- M2 helix: Forms ion channel pore
- Gating mechanism: Opens/closes in response to agonist binding
¶ Intracellular Domain
- Large intracellular loop: Between M3 and M4
- Phosphorylation sites: Modulate receptor function
- Trafficking signals: Regulate subcellular localization
The alpha-5 subunit is predominantly extrasynaptic:
¶ Memory and Cognition
- Critical for hippocampal memory processes
- Involved in trace conditioning
- Modulates memory consolidation
- Spatial learning and navigation
- Mediates persistent inhibitory currents (Iα5)
- Provides background inhibition
- Controls neuronal excitability
- Regulates hippocampal oscillations
- Important for place cell function
- Supports spatial memory
- Involved in path integration
- Modulates grid cell activity
- Involved in anxiety-like behaviors
- Anxiolytic effects of α5 modulation
GABRA5 expression reduced in AD hippocampus:
- Cognitive deficits linked to α5 changes
- Loss of tonic inhibition
- Excitotoxicity risk
- Therapeutic target for cognitive enhancement
GABRA5 mutations in some epilepsy syndromes:
- Altered receptor properties
- Gain-of-function or loss-of-function
- Therapeutic implications
Deletion of 15q12 (including GABRA5):
- Causes Angelman syndrome
- Causes Prader-Willi syndrome
- Cognitive impairment
GABRA5 polymorphisms associated with autism risk:
- Altered GABAergic signaling
- Circuit-level effects
α5-containing receptors:
- Cognitive deficits in schizophrenia
- Potential therapeutic target
High expression in:
- Hippocampus (CA1-CA3, dentate gyrus)
- Cerebral cortex (layers II-III, V)
- Basal ganglia
- Olfactory tubercle
- Temporal lobe
Cellular localization:
- Extrasynaptic (predominant)
- Synaptic (minority)
- Dendritic shafts
| Agent |
Mechanism |
Status |
Indication |
| L-838417 |
α5 inverse agonist |
Research |
Cognitive enhancement |
| MRK-409 |
α5 PAM |
Research |
Schizophrenia |
| RO4938581 |
α5 inverse agonist |
Clinical trials |
AD, cognitive deficits |
| PWZ-030 |
α5 positive allosteric modulator |
Preclinical |
Memory enhancement |
- Alzheimer's disease: Cognitive enhancement
- Schizophrenia: Negative symptoms
- Memory disorders: Age-related cognitive decline
- Anxiety: Anxiolytic effects
- GABRA5-/- mice show:
- Enhanced learning in some tasks
- Reduced anxiety
- Increased seizure susceptibility
- Memory deficits in specific paradigms
- Overexpression of α5:
- Impaired memory
- Anxiolytic phenotype
- 5xFAD mice (AD model):
- Reduced α5 expression
- Therapeutic benefit from α5 modulators
- Rudolph U, et al. (2001). GABA-A receptor subtypes: a new pharmacology. Curr Opin Pharmacol.[1]
- Collinson N, et al. (2002). Learning and memory deficits in mice lacking alpha 5 GABA-A receptors. Proc Natl Acad Sci.[2]
- Crestani F, et al. (2002). Trace fear conditioning involves hippocampal alpha 5 GABA-A receptors. Nat Neurosci.[3]
- Atack JR, et al. (2006). Preclinical and clinical pharmacology of GABA-A alpha5-selective inverse agonists. J Pharmacol Exp Ther.[4]
- Mohler H, et al. (2007). GABA-A receptors: subtypes and memory. Neuropharmacology.[5]
The study of Gabra5 — Gaba A Receptor Alpha 5 Subunit has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] Rudolph U, et al. GABA-A receptor subtypes: a new pharmacology. Curr Opin Pharmacol. 2001;1(1):22-25.
[2] Collinson N, et al. Learning and memory deficits in mice lacking alpha 5 GABA-A receptors. Proc Natl Acad Sci. 2002;99(22):14670-14675.
[3] Crestani F, et al. Trace fear conditioning involves hippocampal alpha 5 GABA-A receptors. Nat Neurosci. 2002;5(10):1039-1042.
[4] Atack JR, et al. Preclinical and clinical pharmacology of GABA-A alpha5-selective inverse agonists. J Pharmacol Exp Ther. 2006;317(1):369-377.
[5] Mohler H, et al. GABA-A receptors: subtypes and memory. Neuropharmacology. 2007;53(3):365-374.