GABA-B Receptor Subunit 2

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GABA-B Receptor Subunit 2 — Protein

<table class="infobox infobox-protein">
<tr><th class="infobox-header" colspan="2">GABA-B Receptor Subunit 2 (GABBR2)</th></tr>
<tr><td class="label">Protein Name</td><td><strong>GABA-B Receptor Subunit 2</strong></td></tr>
<tr><td class="label">Gene</td><td>[GABBR2](/genes/gabbr2)</td></tr>
<tr><td class="label">UniProt</td><td><a href="https://www.uniprot.org/uniprot/O75899" target="_blank">O75899</a></td></tr> [@jo2014]
<tr><td class="label">PDB</td><td><a href="https://www.rcsb.org/structure/7C7Q" target="_blank">7C7Q</a></td></tr>
<tr><td class="label">Mass</td><td>105.4 kDa (941 amino acids)</td></tr>
<tr><td class="label">Family</td><td>Class C GPCR</td></tr>
<tr><td class="label">Diseases</td><td>[Alzheimer's Disease](/diseases/alzheimers), Epileptic Encephalopathy, Rett-like Syndrome</td></tr>
<tr><td class="label">Localization</td><td>Plasma membrane (pre- and postsynaptic)</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>

Overview

GABA-B Receptor Subunit 2 is the G-protein coupling and trafficking subunit of the heterodimeric GABA-B receptor. While [GABBR1](/proteins/gabbr1-protein) 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](/genes/gabbr2), this subunit also interacts with auxiliary KCTD subunits that fine-tune receptor kinetics.

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GABA-B Receptor Subunit 2 — Protein

Overview

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.

Structure

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

G-Protein Coupling

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

KCTD Auxiliary Subunits

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.

Function

Signal Transduction

GABBR2-mediated G-protein activation produces:

Gαi pathway: Inhibits adenylyl cyclase → decreases cAMP → reduces PKA activity → decreases [CREB](/genes/creb1) 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

Trafficking Function

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

Role in Disease

Epileptic Encephalopathy

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

Alzheimer's Disease

GABBR2 contributes to [AD](/diseases/alzheimers-disease) through altered inhibitory balance:

Reduced GABBR2 protein in hippocampal CA1 of AD patients
Tonic GABA release from reactive [astrocytes](/entities/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

External Links

[UniProt: O75899](https://www.uniprot.org/uniprot/O75899)
[PDB: 7C7Q](https://www.rcsb.org/structure/7C7Q)
[IUPHAR: GABA-B2](https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=240)

References

[Unknown, Gassmann & Bettler, Regulation of neuronal GABA-B receptor functions by subunit composition (2012) (2012)](https://doi.org/10.1038/nrn3351)

[Schwenk et al., Native GABA-B receptors are heteromultimers with a family of auxiliary subunits (2010) (2010)](https://doi.org/10.1038/nature09321)

[Yoo et al., GABBR2 mutations determine phenotype in Rett syndrome and epileptic encephalopathy (2017) (2017)](https://doi.org/10.1002/ana.24830)

[Mao et al., Cryo-EM structures of inactive and active GABA-B receptor (2020) (2020)](https://doi.org/10.1038/s41422-020-0350-5)

[Jo et al., GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease (2014) (2014)](https://doi.org/10.1038/nm.3639)

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GABA-B Receptor Subunit 2 — Protein

GABA-B Receptor Subunit 2 — Protein

Overview

GABA-B Receptor Subunit 2 — Protein

Overview

Structure

Domain Organization

G-Protein Coupling

KCTD Auxiliary Subunits

Function

Signal Transduction

Trafficking Function

Role in Disease

Epileptic Encephalopathy

Alzheimer's Disease

See Also

External Links

References