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Nat Commun January 1, 2020; 11 (1): 5369.

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

Gielen M , Barilone N , Corringer PJ .

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.

PubMed ID: 33097732
PMC ID: PMC7585415
Article link: Nat Commun

Genes referenced: ecd gabarap tbc1d8

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References [+] :
Bright, Profound desensitization by ambient GABA limits activation of δ-containing GABAA receptors during spillover. 2011, Pubmed