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Journal Articles Nature Communications Year : 2020

The desensitization pathway of GABAA receptors, one subunit at a time

Abstract

GABAA receptors mediate most inhibitory synaptic transmission in the brain of vertebrates. Following GABA binding and fast activation, these receptors undergo a slower desensitization, whose conformational pathway remains largely elusive. To explore the mechanism of desensitization, we used concatemeric α1β2γ2 GABAA receptors to selectively introduce gain-of-desensitization mutations one subunit at a time. A library of twenty-six mutant combinations was generated and their bi-exponential macroscopic desensitization rates measured. Introducing mutations at the different subunits shows a strongly asymmetric pattern with a key contribution of the γ2 subunit, and combining mutations results in marked synergistic effects indicating a non-concerted mechanism. Kinetic modelling indeed suggests a pathway where subunits move independently, the desensitization of two subunits being required to occlude the pore. Our work thus hints towards a very diverse and labile conformational landscape during desensitization, with potential implications in physiology and pharmacology.
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pasteur-03088067 , version 1 (25-12-2020)

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Marc Gielen, Nathalie Barilone, Pierre-Jean Corringer. The desensitization pathway of GABAA receptors, one subunit at a time. Nature Communications, 2020, 11 (1), pp.5369. ⟨10.1038/s41467-020-19218-6⟩. ⟨pasteur-03088067⟩
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