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| Protein Name | GABA-B Receptor Subunit 2 |
| Gene | [GABBR2](/genes/gabbr2) |
| UniProt | O75899 |
| PDB | 7C7Q |
| Mass | 105.4 kDa (941 amino acids) |
| Family | Class C GPCR |
| Diseases | [Alzheimer's Disease](/diseases/alzheimers), Epileptic Encephalopathy, Rett-like Syndrome |
| Localization | Plasma membrane (pre- and postsynaptic) |
GABA-B Receptor Subunit 2 is the G-protein coupling and trafficking subunit of the heterodimeric GABA-B receptor. While GABBR1 provides the ligand-binding domain, GABBR2 is essential for receptor surface expression and for transducing GABA binding into intracellular signaling through Gi/o heterotrimeric G-proteins. Encoded by GABBR2, this subunit also interacts with auxiliary KCTD subunits that fine-tune receptor kinetics.
De novo gain-of-function mutations in GABBR2's transmembrane domain cause severe epileptic encephalopathy and Rett-like neurodevelopmental syndromes, underscoring its critical role in inhibitory neurotransmission.
¶ Domain Organization
- Venus flytrap domain (VFT, residues 1-440): Structurally homologous to GABBR1 VFT but does NOT bind GABA; instead functions as an allosteric modulator
- Cysteine-rich domain (CRD, residues 441-520): Connects VFT to transmembrane domain
- Heptahelical transmembrane domain (TMD, residues 521-770): Seven-pass transmembrane domain that couples to Gi/o proteins upon receptor activation
- C-terminal intracellular domain (residues 771-941): Contains the coiled-coil domain for GABBR1 dimerization and binding sites for KCTD auxiliary subunits
Unlike GABBR1, GABBR2's TMD is the functional G-protein coupling unit:
- Intracellular loops 2 and 3 contact the Gαi subunit
- Agonist binding to GABBR1 VFT induces conformational change transmitted across the heterodimer interface to GABBR2's TMD
- The activated GABBR2 TMD catalyzes GDP→GTP exchange on Gαi, releasing Gβγ
GABBR2's C-terminus binds KCTD proteins that modulate receptor function:
| KCTD |
Effect |
Mechanism |
| KCTD8 |
Sustained signaling |
Prevents desensitization |
| KCTD12 |
Fast desensitization |
Accelerates Gβγ-GIRK uncoupling |
| KCTD12b |
Fast desensitization |
Similar to KCTD12 (rodent-specific) |
| KCTD16 |
Sustained signaling |
Counteracts KCTD12 effects |
Different brain regions express different KCTD complements, creating region-specific GABA-B receptor kinetics.
GABBR2-mediated G-protein activation produces:
- Gαi pathway: Inhibits adenylyl cyclase → decreases cAMP → reduces PKA activity → decreases CREB phosphorylation
- Gβγ pathway (postsynaptic): Activates Kir3.1/3.2 (GIRK1/2) channels → K+ efflux → membrane hyperpolarization → slow IPSP
- Gβγ pathway (presynaptic): Directly inhibits CaV2.1 (P/Q-type) and CaV2.2 (N-type) Ca2+ channels → reduced neurotransmitter vesicle release
- Gβγ pathway: Activates PLCβ in some contexts → IP3 production → intracellular Ca2+ mobilization
GABBR2 is essential for surface expression:
- Masks the RSRR ER-retention signal on GABBR1, allowing the heterodimer to pass ER quality control
- GABBR2 expressed alone can reach the surface, but cannot signal without GABBR1
- The coiled-coil interaction is necessary and sufficient for masking the retention signal
De novo GABBR2 mutations cause gain-of-function receptor activity:
- S695I (TM5): Causes constitutive receptor activation, leading to excessive GIRK channel activation and Rett-like phenotype with seizures
- I705N (TM5): Severe epileptic encephalopathy with intractable seizures
- A567T (TM3): Altered transmembrane helix packing affecting G-protein coupling
- These mutations enhance basal activity of the receptor, chronically activating inhibitory pathways
GABBR2 contributes to AD through altered inhibitory balance:
- Reduced GABBR2 protein in hippocampal CA1 of AD patients
- Tonic GABA release from reactive astrocytes overstimulates extrasynaptic GABA-B receptors
- GABA-B receptor antagonists improve synaptic plasticity and memory in AD mouse models
- KCTD composition changes in AD brain may alter GABA-B receptor desensitization kinetics