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A novel GABA(A) receptor pharmacology: drugs interacting with the ?(+) ?(-) interface.

ABSTRACT: GABA(A) receptors are ligand-gated chloride channels composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to a multiplicity of GABA(A) receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution; and pharmacology. Most of these receptors are composed of two ?, two ? and one ?2 subunits. GABA(A) receptors are the site of action of a variety of pharmacologically and clinically important drugs, such as benzodiazepines, barbiturates, neuroactive steroids, anaesthetics and convulsants. Whereas GABA acts at the two extracellular ?(+) ?(-) interfaces of GABA(A) receptors, the allosteric modulatory benzodiazepines interact with the extracellular ?(+) ?2(-) interface. In contrast, barbiturates, neuroactive steroids and anaesthetics seem to interact with solvent accessible pockets in the transmembrane domain. Several benzodiazepine site ligands have been identified that selectively interact with GABA(A) receptor subtypes containing ?2??2, ?3??2 or ?5??2 subunits. This indicates that the different ? subunit types present in these receptors convey sufficient structural differences to the benzodiazepine binding site to allow specific interaction with certain benzodiazepine site ligands. Recently, a novel drug binding site was identified at the ?(+) ?(-) interface. This binding site is homologous to the benzodiazepine binding site at the ?(+) ?2(-) interface and is thus also strongly influenced by the type of ? subunit present in the receptor. Drugs interacting with this binding site cannot directly activate but only allosterically modulate GABA(A) receptors. The possible importance of such drugs addressing a spectrum of receptor subtypes completely different from that of benzodiazepines is discussed.

SUBMITTER: Sieghart W

PROVIDER: S-EPMC3417481 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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A novel GABA(A) receptor pharmacology: drugs interacting with the α(+) β(-) interface.

Sieghart Werner W Ramerstorfer Joachim J Sarto-Jackson Isabella I Varagic Zdravko Z Ernst Margot M

British journal of pharmacology 20120501 2

GABA(A) receptors are ligand-gated chloride channels composed of five subunits that can belong to different subunit classes. The existence of 19 different subunits gives rise to a multiplicity of GABA(A) receptor subtypes with distinct subunit composition; regional, cellular and subcellular distribution; and pharmacology. Most of these receptors are composed of two α, two β and one γ2 subunits. GABA(A) receptors are the site of action of a variety of pharmacologically and clinically important ...[more]

PMID: 22074382

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Project description:Background and purposeThe binding of transmitter to specialized binding pockets leads to rearrangements in the structure of the receptor eventually resulting in channel opening. We used voltage-clamp fluorometry to investigate the pharmacological basis and biophysical processes that underlie structural changes at the transmitter binding site of the rat ?1?2?2L GABA(A) receptor.Experimental approachSimultaneous electrophysiological and site-specific fluorescence measurements were conducted on receptors expressed in Xenopus oocytes and labelled with an environmentally-sensitive fluorophore, Alexa 546 maleimide, at the ?1L127C site.Key resultsReceptors activated by GABA demonstrate a concentration-dependent increase in fluorescence intensity, indicating that the environment surrounding the fluorophore becomes less polar upon activation. Qualitatively similar responses were observed with other GABA site ligands such as piperidine-4-sulphonic acid, muscimol, ?-alanine and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol. Fluorescence changes were not affected by the direction of current flow. During long applications of GABA significant desensitization developed, which was not accompanied by additional changes in fluorescence. Pentobarbital was an efficacious agonist of the labelled mutant receptor but did not cause changes in fluorescence. Direct activation by etomidate or the steroid allopregnanolone also did not result in fluorescence changes. Functional potentiation of GABA-activated receptors by allopregnanolone or etomidate enhanced both the GABA-elicited functional response and the fluorescence change. In contrast, potentiation by pentobarbital was not accompanied by an enhanced fluorescence response.Conclusions and implicationsThe data indicate that there is no direct correlation between current flow or position of the activation gate and the structural changes as detected by Alexa 546-labelled ?1L127C?2?2L GABA(A) receptors. Channel potentiation by pentobarbital qualitatively differs from potentiation by etomidate or allopregnanolone.

Dataset Information

A novel GABA(A) receptor pharmacology: drugs interacting with the ?(+) ?(-) interface.

Publications

A novel GABA(A) receptor pharmacology: drugs interacting with the α(+) β(-) interface.

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