Molecular biology of GABA _A receptors

Abstract

The major type of receptor for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), called the GABAA receptor, is a member of a gene superfamily of ligand-gated ion channels. This receptor is a hetero-oligomeric protein composed of several distinct polypeptide types (alpha, beta, gamma, and delta). Molecular cloning of these polypeptides reveals that they show 20-40% identity with each other, and 10-20% identity with polypeptides of the nicotinic acetylcholine receptors and strychnine-sensitive glycine receptor. Each polypeptide type is also represented by a family of genes whose members have 60-80% amino acid sequence identity. Regions of conserved and variable amino acid sequence suggest structural and functional domains within each polypeptide. All of the polypeptides when expressed in heterologous cells produce GABA-activated chloride channels, and the different subtypes express different pharmacological properties. The distributions of mRNAs for the different GABAA receptor polypeptides and their subtypes show significant brain regional variation consistent with pharmacological and biochemical evidence for receptor heterogeneity. Subpopulations of GABAA receptors with different cellular and regional locations show differential sensitivity to GABA, to modulators like steroids, to physiological regulation, to disease processes, and to pharmacological manipulation by drugs such as benzodiazepines. The properties of the different subpopulations of GABAA receptors are determined by which one or more of the different polypeptides and their subtypes are expressed in a given cell to produce a variety of different oligomeric protein structures. Molecular cloning techniques have produced rapid advances in understanding the GABAA receptor protein family.

Extrasynaptic localization of GABA in the developing mouse cerebellum

“…In the adult central nervous system (CNS), γ-amino butyric acid (GABA) is a predominant neurotransmitter which is synaptically released, mediates fast inhibitory synaptic transmission, and regulates excitatory activity of neurons (Olsen and Tobin, 1990;Macdonald and Olsen, 1994). Recent studies have revealed that GABA serves as an excitatory transmitter during brain development, and induces trophic responses, such as regulation of cell proliferation, cell migration, axonal growth, synapse formation, steroid-mediated sexual differentiation and cell death (Varju et al, 2001;Ben-Ari, 2002;McCarthy et al, 2002;Owens and Kriegstein, 2002).…”

Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study

“…Molecular cloning studies revealed five different but homologous receptor subunits (a,/3, y, 6, and p), each of which exists in the brain in different variants. Additional diversity arises from RNA splicing [35,36,46,52,71]. In recombinant expression studies, the association of different cloned subunit variants leads to functional diversity of the GABA A receptor complexes with respect to conductance and gating properties of the chloride channels, the allosteric modulation by benzodiazepines and the sensitivity for agonists.…”

“…In recombinant expression studies, the association of different cloned subunit variants leads to functional diversity of the GABA A receptor complexes with respect to conductance and gating properties of the chloride channels, the allosteric modulation by benzodiazepines and the sensitivity for agonists. The type of a subunit, in combination with a /3 and a y2 subunit, is a major determinant of the type of benzodiazepine pharmacology displayed [13,35,39,52,[57][58][59]72]. The GABAAR affinity and efficacy for benzodiazepines is also influenced by the ,/ subunit present, with receptors containing a 72 subunit exibiting the classical benzodiazepine modulation [59,63,76].…”

Developmental localization of potassium chloride co-transporter 2 (KCC2) in the Purkinje cells of embryonic mouse cerebellum

“…In the adult central nervous system (CNS), γ-amino butyric acid (GABA) mediates fast inhibitory synaptic transmission and regulates the excitatory activity of neurons (Olsen and Tobin, 1990;Macdonald and Olsen, 1994). In the immature CNS, on the other hand, GABA is an excitatory transmitter and is involved in controlling morphogenesis (Ben-Ari, 2002;McCarthy et al, 2002;Owens and Kriegstein, 2002;Represa and Ben-Ari, 2005).…”