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

Marc Gielen (), Nathalie Barilone and Pierre-Jean Corringer
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Marc Gielen: Channel Receptors Unit, Institut Pasteur, CNRS UMR 3571
Nathalie Barilone: Channel Receptors Unit, Institut Pasteur, CNRS UMR 3571
Pierre-Jean Corringer: Channel Receptors Unit, Institut Pasteur, CNRS UMR 3571

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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, the conformational pathway of which 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.

Date: 2020
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DOI: 10.1038/s41467-020-19218-6

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