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Direct Structural Insights into GABA_A Receptor Pharmacology.

ABSTRACT: GABA_A receptors are pentameric ligand-gated ion channels that mediate most fast neuronal inhibition in the brain. In addition to their important physiological roles, they are noteworthy in their rich pharmacology; prominent drugs used for anxiety, insomnia, and general anesthesia act through positive modulation of GABA_A receptors. Direct structural information for how these drugs work was absent until recently. Efforts in structural biology over the past few years have revealed how important drug classes and natural products interact with the GABA_A receptor, providing a foundation for studies in dynamics and structure-guided drug design. Here, we review recent developments in GABA_A receptor structural pharmacology, focusing on subunit assemblies of the receptor found at synapses.

SUBMITTER: Kim JJ

PROVIDER: S-EPMC8122054 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Direct Structural Insights into GABAA Receptor Pharmacology.

Kim Jeong Joo JJ Hibbs Ryan E RE

Trends in biochemical sciences 20210303 6

GABAA receptors are pentameric ligand-gated ion channels that mediate most fast neuronal inhibition in the brain. In addition to their important physiological roles, they are noteworthy in their rich pharmacology; prominent drugs used for anxiety, insomnia, and general anesthesia act through positive modulation of GABAA receptors. Direct structural information for how these drugs work was absent until recently. Efforts in structural biology over the past few years have reve ...[more]

PMID: 33674151

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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 α1β2γ2L 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 α1L127C 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, β-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 α1L127Cβ2γ2L GABA(A) receptors. Channel potentiation by pentobarbital qualitatively differs from potentiation by etomidate or allopregnanolone.

Dataset Information

Direct Structural Insights into GABA_A Receptor Pharmacology.

Publications

Direct Structural Insights into GABA<sub>A</sub> Receptor Pharmacology.

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