The ‘Abc’ of Gaba Receptors: A Brief Review

Abstract

1. In the mammalian central nervous system, GABA is the main inhibitory neurotransmitter. GABA is a highly flexible molecule and, thus, can exist in many low-energy conformations. Conformationally restricted analogues of GABA have been used to help identify three major GABA receptors, termed GABAA, GABAB and GABAC receptors. 2. GABAA and GABAC receptors are members of a super-family of transmitter-gated ion channels that include nicotinic acetylcholine, strychnine-sensitive glycine and 5HT3 receptors. GABAA receptors are hetero-oligomeric Cl- channels that are selectively blocked by the alkaloid bicuculline and modulated by steroids, barbiturates and benzodiazepines. To date, 16 human GABAA receptor cDNA have been cloned. 3. GABAB receptors are seven transmembrane receptors that are coupled to G-proteins and activate second messenger systems and Ca2+ and K+ ion channels. To date, three GABAB receptor proteins have been cloned and these resemble metabotropic glutamate receptors. GABAB receptors are hetero-oligomeric receptors made up of a mixture of a combination of the subunits. These receptors are selectively activated by (-)-baclofen and CCGP27492 and are blocked by phaclofen, the phosphonic acid analogue of baclofen. 4. In contrast, GABAC receptors represent a relatively simple form of transmitter-gated Cl- channel made up of a single type of protein subunit. Two human GABAC receptor cDNA have been cloned. These receptors are not blocked by bicuculline nor are they modulated by steroids, barbiturates or benzodiazepines. Instead, GABAC receptors are selectively activated by the conformationally restricted analogues of GABA in the folded conformation cis-4-aminocrotonic acid and (1s,2R)-2-(aminomethyl)-1-carboxycyclopropane. (1,2,5,6-Tetrahydropyridine-4-yl)methylphosphinic acid, a methylphosphinic acid analogue of GABA in a partially folded conformation, is a selective antagonist at GABAC receptors.

GABA Release and Uptake Regulate Neuronal Precursor Migration in the Postnatal Subventricular Zone

“…For these experiments, GABA was pressure applied for 16.5 min onto neuronal precursors recorded in voltage clamp at a holding potential of Ϫ70 mV in acute SVZ slices. GABA can activate both ionotropic GABA A and GABA C Rs, as well as G-protein-coupled GABA B Rs (Chebib and Johnston, 1999). The effect of GABA was mediated by the activation of GABA A Rs, because applications of 10 M GABA in the presence of the GABA A R antagonist bicuculline (100 M; the control is in the presence of bicuculline) or applications of the GABA B R agonist baclofen (10 M) did not affect the speed of cell migration ( p Ͼ 0.1 in each case; n ϭ 45 cells from three slices per condition) (Fig.…”

Studies on the Anticonvulsant Activity and Influence on GABA-ergic Neurotransmission of 1,2,4-Triazole-3-thione- Based Compounds

“…The most important neurotransmitter inhibiting neuronal processes is γ-aminobutyric acid (GABA). Among three types of GABA receptors (i.e., GABA A , GABA B , GABA C ), the main role in preventing seizures is played by the GABA A receptors [23,24]. Antiepileptic drugs acting directly on GABA A receptors, enhancing the synthesis or inhibiting the metabolism of GABA, as well as blocking the reuptake of GABA from the synaptic cleft, cause an increase in the GABA-ergic neurotransmission [25].…”

The Neurobiology of Opiate Motivation

“…On the other hand, GABA B receptors-which are metabotropic, G-protein-coupled receptors that activate potassium ion channels and/or inhibit calcium channels-mediate slow, prolonged inhibition and are thought to lie primarily on VTA dopamine cells as suggested by antibody staining (Chelib and Johnson 1999;Wirtshafter and Sheppard 2001) and the specific actions of GABA B receptor agonists on dopamine cells (Olpe et al 1977;Kalivas et al 1990;Laviolette and van der Kooy 2001). Figure 2 summarizes the various VTA cell and receptor subtype interrelationships.…”