GABAB receptor

Functions

GABABRs stimulate the opening of K+ channels, specifically GIRKs, which brings the neuron closer to the equilibrium potential of K+. This reduces the frequency of action potentials which reduces neurotransmitter release. Thus GABAB receptors are usually considered as inhibitory receptors.

GABAB receptors can also function as an excitatory receptor and facilitate neurotransmitter release via increasing the activity of CaV2.3 channels.

GABAB receptors usually reduces the activity of adenylyl cyclase and Ca2+ channels by using G-proteins with Gi/G0 α subunits.

GABAB receptors are involved in behavioral actions of ethanol, gamma-hydroxybutyric acid (GHB), and possibly in pain. Recent research suggests that these receptors may play an important developmental role.

Structure

GABAB receptors are similar in structure to and in the same receptor family with metabotropic glutamate receptors. There are two subunits of the receptor, GABAB1 and GABAB2, and these appear to assemble as obligate heterodimers in neuronal membranes by linking up by their intracellular C termini. In the mammalian brain, two predominant, differentially expressed isoforms of the GABAB1 are transcribed from the Gabbr1 gene, GABAB(1a) and GABAB(1b), which are conserved in different species including humans. This might potentially offer more complexity in terms of the function due to different composition of the receptor. Cryo-electron microscopy structures of the full length GABAB receptor in different conformational states from inactive apo to fully active have been obtained. Unlike Class A and B GPCRs, phospholipids bind within the transmembrane bundles and allosteric modulators bind at the interface of GABAB1 and GABAB2 subunits.

Ligands

Agonists

• GABA
• Baclofen is a GABA analogue which acts as a selective agonist of GABAB receptors, and is used as a muscle relaxant. However, it can aggravate absence seizures, and so is not used in epilepsy.
• gamma-Hydroxybutyrate (GHB)
• Phenibut
• 4-Fluorophenibut
• Isovaline
• 3-Aminopropylphosphinic acid
• Lesogaberan
• SKF-97541: 3-Aminopropyl(methyl)phosphinic acid, 10× more potent than baclofen as GABAB agonist, but also GABAA-ρ antagonist
• Taurine
• CGP-44532

Positive allosteric modulators

• ASP-8062
• CGP-7930
• BHFF
• Fendiline
• BHF-177
• BSPP
• GS-39783
• INDV-1000

Antagonists

• Homotaurine
• Ginsenosides
• 2-Hydroxysaclofen
• Saclofen
• Phaclofen
• SCH-50911
• 2-Phenethylamine
• CGP-35348
• CGP-52432: 3-([(3,4-Dichlorophenyl)methyl]amino]propyl) diethoxymethyl)phosphinic acid, CAS# 139667-74-6
• CGP-55845: (2S)-3-([(1S)-1-(3,4-Dichlorophenyl)ethyl]amino-2-hydroxypropyl)(phenylmethyl)phosphinic acid, CAS# 149184-22-5
• SGS-742

References

References

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