GABA_B receptors (GABA_BR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels. The changing potassium concentrations hyperpolarize the cell at the end of an action potential. The reversal potential of the GABA_B-mediated IPSP (inhibitory postsynaptic potential) is –100 mV, which is much more hyperpolarized than the GABA_A IPSP. GABA_B receptors are found in the central nervous system and the autonomic division of the peripheral nervous system. The receptors were first named in 1981 when their distribution in the CNS was determined, which was determined by

Norman Bowery Professor Norman Bowery , (1944 – 25 October 2016) was a British pharmacologist and former Head of Division of Neuroscience and Chair of Pharmacology at the University of Birmingham from 1995 to 2004. He was president of the British Pharmacologi ...

and his team using radioactively labelled baclofen.

Functions

GABA_BRs 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 A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

release. Thus GABA_B receptors are inhibitory receptors. GABA_B receptors also reduces the activity of adenylyl cyclase and Ca²⁺ channels by using G-proteins with G_i/G₀ α subunits. GABA_B receptors are involved in behavioral actions of ethanol,

gamma-hydroxybutyric acid ''gamma''-Hydroxybutyric acid (or γ-hydroxybutyric acid (GHB), also known as 4-hydroxybutanoic acid) is a naturally occurring neurotransmitter and a depressant drug. It is a precursor to GABA, glutamate, and glycine in certain brain areas. ...

(GHB), and possibly in pain. Recent research suggests that these receptors may play an important developmental role. 6VJM GABAB Receptor dimer inactive

Structure

GABA_B Receptors are similar in structure to and in the same receptor family with metabotropic glutamate receptors.MRC (Medical Research Council). 2003.
Glutamate receptors: Structures and functions.
University of Brisotol Centre for Synaptic Plasticity. There are two subunits of the receptor, GABA_B1 and GABA_B2, and these appear to assemble as

heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

s in neuronal membranes by linking up by their intracellular C termini. In the mammalian brain, two predominant, differentially expressed isoforms of the GABA_B1 are transcribed from the Gabbr1 gene, GABA_B(1a) and GABA_B(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 GABA_B 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 GABA_B1 and GABA_B2 subunits.

Ligands

Agonists

* GABA * Baclofen is a GABA analogue which acts as a selective agonist of GABA_B receptors, and is used as a muscle relaxant. However, it can aggravate

absence seizure Absence seizures are one of several kinds of generalized seizures. These seizures are sometimes referred to as petit mal seizures (from the French for "little illness", a term dated in the late 18th century). Absence seizures are characterized by ...

s, and so is not used in epilepsy. * ''gamma''-Hydroxybutyrate (GHB) *

Phenibut Phenibut, sold under the brand names Anvifen, Fenibut, and Noofen among others, is a central nervous system depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications. It is usually taken ...

4-Fluorophenibut 4-Fluorophenibut (developmental code name CGP-11130; also known as β-(4-fluorophenyl)-γ-aminobutyric acid or β-(4-fluorophenyl)-GABA) is a GABAB receptor agonist which was never marketed. It is selective for the GABAB receptor over the GAB ...

Isovaline Isovaline is a rare amino acid transported to earth by the Murchison meteorite, which landed in Australia in 1969. The discovery of isovaline in the biosphere demonstrates an extraterrestrial origin of amino acids and has been linked to the homoc ...

3-Aminopropylphosphinic acid 3-Aminopropylphosphinic acid, also known in the literature as 3-APPA or CGP 27492, is a compound used in scientific research which acts as an agonist at the GABAB receptor. It is part of a class of phosphinic acid GABAB agonists, which also incl ...

Lesogaberan Lesogaberan (AZD-3355) was an experimental drug candidate developed by AstraZeneca for the treatment of gastroesophageal reflux disease (GERD). As a GABAB receptor agonist, it has the same mechanism of action as baclofen, but is anticipated to ...

* SKF-97541: 3-Aminopropyl(methyl)phosphinic acid, 10x more potent than baclofen as GABA_B agonist, but also GABA_A-rho antagonist * CGP-44532

Positive Allosteric Modulators

* CGP-7930 *

BHFF BHFF is a compound used in scientific research which acts as a positive allosteric modulator at the GABAB receptor. It has anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces an ...

* Fendiline *

BHF-177 BHF-177 is a compound used in scientific research which acts as a positive allosteric modulator at the GABAB receptor. It was shown to reduce self-administration of nicotine Nicotine is a natural product, naturally produced alkaloid in the ...

* BSPP *

GS-39783 GS-39783 is a compound used in scientific research which acts as a positive allosteric modulator at the GABAB receptor. It has been shown to produce anxiolytic effects in animal studies, and reduces self-administration of alcohol, cocaine and n ...

Antagonists

* Homotaurine * Ginsenosides * 2-OH-saclofen *

Saclofen Saclofen is a competitive Receptor antagonist, antagonist for the GABAB receptor, GABAB receptor. This drug is an analogue of the GABAB agonist baclofen. The GABAB receptor is heptahelical receptor, expressed as an obligate heterodimer, which cou ...

Phaclofen Phaclofen, or phosphonobaclofen, is a selective antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ...

SCH-50911 SCH-50911 is a selective GABAB antagonist. Its main applications are in pharmacology research. SCH-50911 also acts as an anticonvulsant under normal conditions. SCH-50911 induces acute withdrawal syndrome in GHB-dependent rats, similar to the de ...

2-Phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...

* CGP-35348 * CGP-52432: 3-( 3,4-Dichlorophenyl)methylmino]propyl) diethoxymethyl)phosphinic acid, CAS# 139667-74-6 * CGP-55845: (2S)-3-( 1S)-1-(3,4-Dichlorophenyl)ethylmino-2-hydroxypropyl)(phenylmethyl)phosphinic acid, CAS# 149184-22-5 * SGS-742

References

External links

{{G protein-coupled receptors, g3 G protein-coupled receptors GABA