GABA_B receptors (GABA_BR) are G-protein coupled receptors for

gamma-aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

(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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

and the autonomic division of the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of Bilateria, bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside t ...

. 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.

Functions

GABA_BRs stimulate the opening of K⁺ channels, specifically GIRKs, which brings the

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

closer to the

equilibrium potential In a biological membrane, the reversal potential is the membrane potential at which the direction of ionic current reverses. At the reversal potential, there is no net flow of ions from one side of the membrane to the other. For channels that are pe ...

of K⁺. This reduces the frequency of

action potential An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

s which reduces

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

release. Thus GABA_B receptors are inhibitory receptors. GABA_B receptors also reduces the activity of

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

and Ca²⁺ channels by using G-proteins with G_i/G₀ α subunits. GABA_B receptors are involved in behavioral actions of

ethanol Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...

, gamma-hydroxybutyric acid (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 obligate

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer 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 ...

s in neuronal membranes by linking up by their intracellular C termini. In the mammalian brain, two predominant, differentially expressed

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

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 Cryogenic electron microscopy (cryo-EM) is a transmission electron microscopy technique applied to samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An ...

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 GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

* Baclofen is a GABA analogue which acts as a selective agonist of GABA_B receptors, and is used as a

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

. However, it can aggravate

absence seizure Absence seizures are one of several kinds of generalized seizures. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy (i.e. without a notable postictal state). Absence ...

s, and so is not used in

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

. * ''gamma''-Hydroxybutyrate (GHB) *

Phenibut Phenibut, sold under the brand name Anvifen among others, is a central nervous system (CNS) depressant with anxiolytic effects, and is used to treat anxiety, insomnia, and for a variety of other indications. It is usually taken oral administrat ...

* 4-Fluorophenibut * Isovaline * 3-Aminopropylphosphinic acid * Lesogaberan * SKF-97541: 3-Aminopropyl(methyl)phosphinic acid, 10× more potent than baclofen as GABA_B agonist, but also GABA_A-ρ antagonist *

Taurine Taurine (), or 2-aminoethanesulfonic acid, is a naturally occurring amino sulfonic acid that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine. It is named after Latin (cogna ...

* CGP-44532

Positive allosteric modulators

* CGP-7930 * BHFF * Fendiline * BHF-177 * BSPP * GS-39783

Antagonists

* Homotaurine * Ginsenosides * 2-OH-saclofen * Saclofen * Phaclofen * SCH-50911 * 2-Phenethylamine * 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