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| Protein Name | GABA-B Receptor Subunit 1 |
| Gene | [GABBR1](/genes/gabbr1) |
| UniProt | Q9UBS5 |
| PDB | 4MQE, 7C7Q |
| Mass | 108 kDa (960 amino acids, GABBR1a isoform) |
| Family | Class C GPCR (metabotropic glutamate receptor family) |
| Diseases | [Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), Epilepsy |
| Localization | Plasma membrane (pre- and postsynaptic), ER (when undimerized) |
GABA-B Receptor Subunit 1 is the ligand-binding component of the heterodimeric GABA-B metabotropic receptor, the principal slow inhibitory receptor in the mammalian CNS. Encoded by GABBR1, this protein forms an obligate heterodimer with GABA-B Receptor Subunit 2 to create functional receptors. GABBR1 contains the orthosteric binding site for GABA and pharmacological agonists such as baclofen.
Two major isoforms — GABBR1a and GABBR1b — arise from alternative promoter usage and differ in their N-terminal sushi domains, which determine subcellular trafficking to axonal versus somatodendritic compartments.
¶ Domain Organization
- Sushi domains (GABBR1a only, residues 1-147): Two complement control protein (CCP) modules that target the receptor to axons for presynaptic localization
- Venus flytrap domain (VFT, residues 148-480): Bilobed domain that undergoes conformational closure upon GABA binding; homologous to periplasmic binding proteins
- Cysteine-rich domain (CRD, residues 481-560): Stabilizes VFT conformational changes and transmits signal to the transmembrane domain
- Heptahelical transmembrane domain (TMD, residues 581-830): Seven transmembrane alpha-helices; does NOT couple to G-proteins (this function is performed by GABBR2)
- C-terminal intracellular domain (residues 831-960): Contains the RSRR ER-retention motif and the coiled-coil domain for GABBR2 heterodimerization
¶ Ligand Binding
The VFT domain binds agonists in its inter-lobe cleft:
- GABA: Natural agonist, binds with ~1 µM affinity in the closed VFT conformation
- Baclofen: Synthetic agonist (p-chlorophenyl-GABA), selective GABA-B agonist
- CGP54626: Competitive antagonist that stabilizes the open VFT conformation
- Cryo-EM structures (7C7Q) reveal the complete heterodimer in active and inactive states
GABBR1 and GABBR2 form the functional receptor through:
- Coiled-coil interaction: C-terminal coiled-coil domains of both subunits intertwine
- VFT-VFT interface: Intersubunit contacts between the two VFT domains stabilize the heterodimer
- ER quality control: The RSRR motif on GABBR1 is masked only when GABBR2 binds, ensuring only heterodimers reach the plasma membrane
GABBR1-containing GABA-B receptors mediate two forms of inhibition:
-
Presynaptic inhibition (autoreceptors and heteroreceptors):
- GABBR1a-containing receptors predominate at presynaptic terminals
- Activation inhibits P/Q-type and N-type Ca2+ channels, reducing neurotransmitter release
- Acts on both GABAergic (autoreceptor) and glutamatergic (heteroreceptor) terminals
-
Postsynaptic inhibition:
- GABBR1b-containing receptors predominate postsynaptically
- Activates Kir3/GIRK K+ channels via Gβγ subunits, generating slow IPSPs
- Produces sustained hyperpolarization lasting hundreds of milliseconds
- APP interaction: GABBR1a sushi domains bind the extracellular domain of APP, forming a complex that influences axonal trafficking and amyloidogenic processing
- Transcriptional regulation: GABBR1 intracellular domain fragments may translocate to the nucleus
- Trophic signaling: GABA-B receptor activation promotes neurite outgrowth during development
GABBR1 dysfunction contributes to AD pathophysiology:
- GABBR1 protein levels decline in hippocampal CA1 and entorhinal cortex in AD
- The GABBR1a-APP interaction is disrupted by amyloid-beta accumulation, impairing axonal GABA-B receptor localization
- Loss of inhibitory GABA-B tone contributes to neuronal hyperexcitability observed in early AD
- Reactive astrocytes release tonic GABA, aberrantly activating extrasynaptic GABA-B receptors
- GABA-B receptor modulation is being explored as a cognitive enhancement strategy in AD
In PD:
- Altered GABBR1 expression in basal ganglia circuits (striatum, globus pallidus, subthalamic nucleus)
- GABA-B receptors on striatopallidal neurons modulate indirect pathway output
- Baclofen affects motor behavior through GABA-B receptors in the basal ganglia