GABAB receptor

Last updated
gamma-aminobutyric acid (GABA) B receptor, 1
Identifiers
SymbolGABBR1
NCBI gene 2550
HGNC 4070
OMIM 603540
RefSeq NM_021905
UniProt Q9UBS5
Other data
Locus Chr. 6 p21.3
Search for
Structures Swiss-model
Domains InterPro
gamma-aminobutyric acid (GABA) B receptor, 2
Identifiers
SymbolGABBR2
Alt. symbolsGPR51
NCBI gene 9568
HGNC 4507
OMIM 607340
RefSeq NM_005458
UniProt O75899
Other data
Locus Chr. 9 q22.1-22.3
Search for
Structures Swiss-model
Domains InterPro

GABAB receptors (GABABR) are G-protein coupled receptors for gamma-aminobutyric acid (GABA), therefore making them metabotropic receptors, that are linked via G-proteins to potassium channels. [1] The changing potassium concentrations hyperpolarize the cell at the end of an action potential. The reversal potential of the GABAB-mediated IPSP (inhibitory postsynaptic potential) is −100 mV, which is much more hyperpolarized than the GABAA IPSP. GABAB receptors are found in the central nervous system and the autonomic division of the peripheral nervous system. [2]

Contents

The receptors were first named in 1981 when their distribution in the CNS was determined, which was determined by Norman Bowery and his team using radioactively labelled baclofen. [3]

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.[ citation needed ] Thus GABAB receptors are inhibitory receptors.

GABAB receptors also reduces the activity of adenylyl cyclase and Ca2+ channels by using G-proteins with Gi/G0 α subunits. [4]

GABAB receptors are involved in behavioral actions of ethanol, [5] [6] gamma-hydroxybutyric acid (GHB), [7] and possibly in pain. [8] Recent research suggests that these receptors may play an important developmental role. [9]

Receptor dimer, inactive apo state, cartoon representation 6VJM GABAB Receptor dimer inactive.png
Receptor dimer, inactive apo state, cartoon representation

Structure

GABAB Receptors are similar in structure to and in the same receptor family with metabotropic glutamate receptors. [10] There are two subunits of the receptor, GABAB1 and GABAB2, [11] and these appear to assemble as obligate heterodimers in neuronal membranes by linking up by their intracellular C termini. [10] 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. [12] This might potentially offer more complexity in terms of the function due to different composition of the receptor. [12] 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. [13] [14] [15] [16] [17] [18] [19]

Ligands

GABA Gamma-Aminobuttersaure - gamma-aminobutyric acid.svg
GABA
GHB 4-Hydroxybutansaure - 4-Hydroxybutanoic acid.svg
GHB
Lesogaberan Lesogaberan.svg
Lesogaberan

Agonists

CGP-7930 CGP-7930 chemical structure.svg
CGP-7930

Positive Allosteric Modulators

Phaclofen Phaclofen.svg
Phaclofen
SCH-50911 SCH-50911.svg
SCH-50911

Antagonists

See also

Related Research Articles

γ-Aminobutyric acid Main inhibitory neurotransmitter in the mammalian brain

γ-Aminobutyric acid, or GABA, is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.

<span class="mw-page-title-main">GABA receptor</span> Receptors that respond to gamma-aminobutyric acid

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory compound in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABAA and GABAB. GABAA receptors are ligand-gated ion channels ; whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptors.

GABA<sub>A</sub> receptor Ionotropic receptor and ligand-gated ion channel

The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic transmission through appropriate developmental processes, specificity to neural cell types, and responsiveness to activity is crucial for the proper functioning of nearly all aspects of the central nervous system (CNS). Upon opening, the GABAA receptor on the postsynaptic cell is selectively permeable to chloride ions (Cl) and, to a lesser extent, bicarbonate ions (HCO3).

The GABAA-rho receptor is a subclass of GABAA receptors composed entirely of rho (ρ) subunits. GABAA receptors including those of the ρ-subclass are ligand-gated ion channels responsible for mediating the effects of gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the brain. The GABAA-ρ receptor, like other GABAA receptors, is expressed in many areas of the brain, but in contrast to other GABAA receptors, the GABAA-ρ receptor has especially high expression in the retina.

GABA gamma-aminobutyric acid (GABA) is a key chemical messenger or a neurotransmitter in the central nervous system, that significantly inhibits neuronal transmission. GABA calms the brain and controls several physiological processes, such as stress, anxiety, and sleep. GABAA receptors are a class of ionotropic receptors that are triggered by GABA. They are made up of five subunits that are assembled in various configurations to create distinct receptor subtypes. The direct influx of chloride ions causes rapid inhibitory responses. GABAB receptors are another type of metabotropic receptor that modifies intracellular signaling pathways to provide slower, sustained inhibitory responses. At synapses, GABAA receptors facilitate rapid inhibitory neurotransmission, whereas GABAB receptor which comprise GABA B1 and GABA B2 subunits—control neurotransmitter release and cellular excitability over a longer period of time. These unique qualities help explain the various ways that GABAergic neurotransmission controls brain communication and neuronal function.

<span class="mw-page-title-main">GABA receptor agonist</span> Category of drug

A GABA receptor agonist is a drug that is an agonist for one or more of the GABA receptors, producing typically sedative effects, and may also cause other effects such as anxiolytic, anticonvulsant, and muscle relaxant effects. There are three receptors of the gamma-aminobutyric acid. The two receptors GABA-α and GABA-ρ are ion channels that are permeable to chloride ions which reduces neuronal excitability. The GABA-β receptor belongs to the class of G-Protein coupled receptors that inhibit adenylyl cyclase, therefore leading to decreased cyclic adenosine monophosphate (cAMP). GABA-α and GABA-ρ receptors produce sedative and hypnotic effects and have anti-convulsion properties. GABA-β receptors also produce sedative effects. Furthermore, they lead to changes in gene transcription.

<i>gamma</i>-Amino-<i>beta</i>-hydroxybutyric acid Anticonvulsant drug

γ-Amino-β-hydroxybutyric acid (GABOB), also known as β-hydroxy-γ-aminobutyric acid (β-hydroxy-GABA), and sold under the brand name Gamibetal among others, is an anticonvulsant which is used for the treatment of epilepsy in Europe, Japan, and Mexico. It is a GABA analogue, or an analogue of the neurotransmitter γ-aminobutyric acid (GABA), and has been found to be an endogenous metabolite of GABA.

<span class="mw-page-title-main">GABBR1</span> Protein-coding gene in the species Homo sapiens

Gamma-aminobutyric acid B receptor, 1 (GABAB1), is a G-protein coupled receptor subunit encoded by the GABBR1 gene.

<span class="mw-page-title-main">GABBR2</span> Protein-coding gene in the species Homo sapiens

Gamma-aminobutyric acid (GABA) B receptor, 2 (GABAB2) is a G-protein coupled receptor subunit encoded by the GABBR2 gene in humans.

<span class="mw-page-title-main">Homotaurine</span> Chemical compound

Homotaurine is a natural sulfonic acid found in seaweed. It is analogous to taurine, but with an extra carbon in its chain. It has GABAergic activity, apparently by mimicking GABA, which it resembles.

<span class="mw-page-title-main">Phaclofen</span> GABAB receptor antagonist

Phaclofen, or phosphonobaclofen, is a selective antagonist for the GABAB receptor. It was the first selective GABAB antagonist discovered, but its utility was limited by the fact that it does not cross the blood brain barrier.

<span class="mw-page-title-main">CGP-7930</span> Chemical compound

CGP-7930 was the first positive allosteric modulator of GABAB receptors described in literature. CGP7930 is also a GABAA receptor positive allosteric modulator and a blocker of Potassium channels.

<span class="mw-page-title-main">GS-39783</span> Chemical compound

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 nicotine.

<span class="mw-page-title-main">BHF-177</span> Chemical compound

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 in animal studies.

<span class="mw-page-title-main">SKF-97,541</span> Chemical compound

SKF-97,541 is a compound used in scientific research which acts primarily as a selective GABAB receptor agonist. It has sedative effects in animal studies and is widely used in research into potential treatment of various types of drug addiction.

<span class="mw-page-title-main">CGP-35348</span> Chemical compound

CGP-35348 is a compound used in scientific research which acts as an antagonist at GABAB receptors.

<span class="mw-page-title-main">Quisqualamine</span> Chemical compound

Quisqualamine is the α-decarboxylated analogue of quisqualic acid, as well as a relative of the neurotransmitters glutamate and γ-aminobutyric acid (GABA). α-Decarboxylation of excitatory amino acids can produce derivatives with inhibitory effects. Indeed, unlike quisqualic acid, quisqualamine has central depressant and neuroprotective properties and appears to act predominantly as an agonist of the GABAA receptor and also to a lesser extent as an agonist of the glycine receptor, due to the facts that its actions are inhibited in vitro by GABAA antagonists like bicuculline and picrotoxin and by the glycine antagonist strychnine, respectively. Mg2+ and DL-AP5, NMDA receptor blockers, CNQX, an antagonist of both the AMPA and kainate receptors, and 2-hydroxysaclofen, a GABAB receptor antagonist, do not affect quisqualamine's actions in vitro, suggesting that it does not directly affect the ionotropic glutamate receptors or the GABAB receptor in any way. Whether it binds to and acts upon any of the metabotropic glutamate receptors like its analogue quisqualic acid however is unclear.

Ionotropic GABA receptors (iGABARs) are ligand-gated ion channel of the GABA receptors class which are activated by gamma-aminobutyric acid (GABA), and include:

<span class="mw-page-title-main">4-Fluorophenibut</span> GABAB receptor agonist and phenibut analogue

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 GABAA receptor (IC50 = 1.70 μM and > 100 μM, respectively). The drug is a GABA analogue and is closely related to baclofen (β-(4-chlorophenyl)-GABA), tolibut (β-(4-methylphenyl)-GABA), and phenibut (β-phenyl-GABA). It is less potent as a GABAB receptor agonist than baclofen but more potent than phenibut.

<span class="mw-page-title-main">3-APPA</span> Chemical compound

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 includes SKF-97,541. It has a binding affinity (pKi) to the GABAB receptor of 8.30.

References

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