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| Symbol | GABBR2 |
| Full Name | Gamma-Aminobutyric Acid Type B Receptor Subunit 2 |
| Chromosome | 9q22.33 |
| NCBI Gene | 9568 |
| Ensembl | ENSG00000136928 |
| OMIM | 607340 |
| UniProt | O75899 |
| Diseases | [Alzheimer's Disease](/diseases/alzheimers), Epilepsy, Rett Syndrome |
| Expression | Cerebral [cortex](/brain-regions/cortex), [Hippocampus](/brain-regions/hippocampus), Thalamus, Cerebellum, Brainstem |
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S695I (Rett-like syndrome, gain-of-function)
I705N (epileptic encephalopathy)
A567T (altered G-protein coupling) |
GABBR2 (Gamma-Aminobutyric Acid Type B Receptor Subunit 2) encodes the GABA-B2 subunit of the metabotropic GABA receptor. While GABBR1 provides the ligand-binding domain, GABBR2 is essential for receptor trafficking to the cell surface and for coupling to intracellular G-protein signaling cascades. The obligate heterodimer formed by GABBR1 and GABBR2 constitutes the functional GABA-B receptor that mediates slow inhibitory neurotransmission throughout the brain.
De novo gain-of-function mutations in GABBR2 have been identified in patients with epileptic encephalopathy and Rett-like phenotypes, establishing this gene as a critical node in inhibitory neurotransmission with relevance to multiple neurological disorders.
The protein encoded by GABBR2 is GABA-B Receptor Subunit 2. See the protein page for detailed structural and functional information.
GABBR2 encodes an 941-amino acid seven-transmembrane domain protein with the following functional roles:
- G-protein coupling: The heptahelical domain of GABBR2 activates Gi/o heterotrimeric G-proteins upon receptor activation
- Surface trafficking: Masks the ER retention signal (RSRR motif) on GABBR1, enabling the heterodimer to exit the ER
- Allosteric modulation: The venus flytrap domain of GABBR2 does not bind GABA but allosterically enhances agonist affinity at GABBR1
- Scaffolding: The C-terminal domain interacts with KCTD proteins (KCTD8, KCTD12, KCTD16) that modulate receptor kinetics and desensitization
Through Gi/o activation, GABBR2-containing receptors regulate:
- Kir3/GIRK channels: Opens inwardly rectifying K+ channels, hyperpolarizing postsynaptic neurons
- Voltage-gated Ca2+ channels: Inhibits CaV2.1 (P/Q-type) and CaV2.2 (N-type) channels at presynaptic terminals
- Adenylyl cyclase: Inhibits cAMP production, reducing PKA activity and CREB phosphorylation
- KCTD-dependent desensitization: KCTD12 binding accelerates receptor desensitization, while KCTD16 promotes sustained signaling
¶ Neurodevelopmental and Epileptic Disorders
De novo GABBR2 mutations cause severe neurodevelopmental phenotypes:
- S695I: Gain-of-function mutation causing Rett-like syndrome with epilepsy, absent speech, and stereotypic hand movements
- I705N: Epileptic encephalopathy with severe intellectual disability
- A567T: Located in the transmembrane domain, alters G-protein coupling efficiency
- These mutations cluster in the heptahelical transmembrane domain, enhancing constitutive receptor activity
GABA-B receptor dysfunction contributes to Alzheimer's disease pathophysiology:
- Decreased GABBR2 protein levels in hippocampal CA1 region of AD brains
- Amyloid-beta oligomers impair GABA-B receptor-mediated synaptic inhibition
- Compensatory upregulation of GABA release from reactive astrocytes activates extrasynaptic GABA-B receptors
- GABA-B receptor antagonists (e.g., CGP55845) improve cognitive performance in AD mouse models
- Addiction: GABBR2 polymorphisms associated with alcohol and nicotine dependence
- Mood disorders: GABA-B receptor agonist baclofen used off-label for anxiety and alcohol use disorder
- Pain: GABA-B receptors in spinal cord modulate nociceptive transmission
GABBR2 is co-expressed with GABBR1 throughout the CNS:
- Cerebral cortex: All cortical layers, enriched in pyramidal neurons and interneurons
- Hippocampus: CA1-CA3 pyramidal cells, dentate granule cells, and interneurons
- Thalamus: Relay and reticular neurons (critical for thalamocortical oscillations)
- Cerebellum: Purkinje cells, granule cells, and molecular layer interneurons
- Brainstem: Locus coeruleus, dorsal raphe nucleus, periaqueductal gray
- Spinal cord: Dorsal horn laminae I-III (nociceptive processing)
GABBR2 expression ratio to GABBR1 varies by region, influencing receptor stoichiometry and signaling kinetics.