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](/genes/gabbr1), this protein forms an obligate heterodimer with [GABA-B Receptor Subunit 2](/proteins/gabbr2-protein) to create functional receptors. GABBR1 contains the orthosteric binding site for [GABA](/mechanisms/gabaergic-signaling-neurodegeneration) 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.
Structure
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
Activates Kir3/GIRK K+ channels via Gβγ subunits, generating slow IPSPs
Produces sustained hyperpolarization lasting hundreds of milliseconds
Non-Canonical Functions
[APP](/entities/app-protein) interaction: GABBR1a sushi domains bind the extracellular domain of [APP](/genes/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
Role in Neurodegenerative Diseases
Alzheimer's Disease
GABBR1 dysfunction contributes to [AD](/diseases/alzheimers-disease) pathophysiology:
GABBR1 protein levels decline in hippocampal CA1 and [entorhinal cortex](/brain-regions/entorhinal-cortex) in AD
The GABBR1a-APP interaction is disrupted by [amyloid-beta](/proteins/amyloid-beta) accumulation, impairing axonal GABA-B receptor localization
Loss of inhibitory GABA-B tone contributes to neuronal hyperexcitability observed in early AD
[Bettler et al., Molecular structure and physiological functions of GABA-B receptors (2004) (2004)](https://doi.org/10.1152/physrev.00036.2003)
[Geng et al., Structural mechanism of ligand activation in human GABA-B receptor (2013) (2013)](https://doi.org/10.1038/nature12725)
[Dinamarca et al., Complex formation of APP with GABA-B receptors links axonal trafficking to amyloidogenic processing (2019) (2019)](https://doi.org/10.1038/s41467-019-09498-2)
[Vigot et al., Differential compartmentalization and distinct functions of GABA-B receptor variants (2006) (2006)](https://doi.org/10.1016/j.neuron.2006.04.013)
[Mao et al., Cryo-EM structures of inactive and active GABA-B receptor (2020) (2020)](https://doi.org/10.1038/s41422-020-0350-5)