GABAB receptor

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.^[1] 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.^[2]

gamma-aminobutyric acid (GABA) B receptor, 1
Identifiers
Symbol	GABBR1
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
Symbol	GABBR2
Alt. symbols	GPR51
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

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

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 release.^{[citation needed]} 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.^[4]

GABA_B 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

Structure

GABA_B receptors are similar in structure to and in the same receptor family with metabotropic glutamate receptors.^[10] There are two subunits of the receptor, GABA_B1 and GABA_B2,^[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 GABA_B1 are transcribed from the Gabbr1 gene, GABA_B(1a) and GABA_B(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 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.^{[13][14][15][16][17][18][19]}

Ligands

GABA

GHB

Lesogaberan

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 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 GABA_B agonist, but also GABA_A-ρ antagonist
• Taurine
• CGP-44532

CGP-7930

Positive allosteric modulators

• CGP-7930^[20][21]
• BHFF
• Fendiline
• BHF-177^[22]
• BSPP
• GS-39783^[23]

Phaclofen

SCH-50911

Antagonists

• Homotaurine^[24]
• Ginsenosides^[25]
• 2-OH-saclofen
• 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^[26][27]

See also

• GABA receptor
• GABA_A receptor