The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes.
The amino acid gamma-aminobutyric-acid (GABA) prevails in the CNS as an inhibitory neurotransmitter that mediates most of its effects through fast GABA-gated Cl(-)-channels (GABAAR). Molecular biology uncovered the complex subunit architecture of this receptor channel, in which a pentameric assembly derived from five of at least 17 mammalian subunits, grouped in the six classes alpha, beta, gamma, delta, sigma and epsilon, permits a vast number of putative receptor isoforms. The subunit composition of a particular receptor determines the specific effects of allosterical modulators of the GABAARs like benzodiazepines (BZs), barbiturates, steroids, some convulsants, polyvalent cations, and ethanol. To understand the physiology and diversity of GABAARs, the native isoforms have to be identified by their localization in the brain and by their pharmacology. In heterologous expression systems, channels require the presence of alpha, beta, and gamma subunits in order to mimic the full repertoire of native receptor responses to drugs, with the BZ pharmacology being determined by the particular alpha and gamma subunit variants. Little is known about the functional properties of the beta, delta, and epsilon subunit classes and only a few receptor subtype-specific substances like loreclezole and furosemide are known that enable the identification of defined receptor subtypes. We will summarize the pharmacology of putative receptor isoforms and emphasize the characteristics of functional channels. Knowledge of the complex pharmacology of GABAARs might eventually enable site-directed drug design to further our understanding of GABA-related disorders and of the complex interaction of excitatory and inhibitory mechanisms in neuronal processing.
Hevers
W
W
Department of Psychiatry, University of Mainz, Germany.
Lüddens
H
H
D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001463:Barbiturates / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D001665:Binding Sites; D018118:Chloride Channels / Q000737:chemistry / Q000145:classification* / Q000187:drug effects / Q000502:physiology; D003292:Convulsants / Q000494:pharmacology; D004594:Electrophysiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000145:classification* / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000737:chemistry / Q000145:classification* / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology; D013379:Substrate Specificity; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000777:Anesthetics; D001463:Barbiturates; D018118:Chloride Channels; D003292:Convulsants; D018755:GABA Agonists; D018756:GABA Antagonists; D046911:Macromolecular Substances; D020033:Protein Isoforms; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D013256:Steroids; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid