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Elife February 16, 2021; 10

A critical residue in the α1M2-M3 linker regulating mammalian GABAA receptor pore gating by diazepam.

Nors JW , Gupta S , Goldschen-Ohm MP .

Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that modulate activity of GABAA receptors (GABAARs), neurotransmitter-gated ion channels critical for synaptic transmission. However, the physical basis of this modulation is poorly understood. We explore the role of an important gating domain, the α1M2-M3 linker, in linkage between the BZD site and pore gate. To probe energetics of this coupling without complication from bound agonist, we use a gain of function mutant (α1L9''Tβ2γ2L) directly activated by BZDs. We identify a specific residue whose mutation (α1V279A) more than doubles the energetic contribution of the BZD positive modulator diazepam (DZ) to pore opening and also enhances DZ potentiation of GABA-evoked currents in a wild-type background. In contrast, other linker mutations have little effect on DZ efficiency, but generally impair unliganded pore opening. Our observations reveal an important residue regulating BZD-pore linkage, thereby shedding new light on the molecular mechanism of these drugs.

PubMed ID: 33591271
PMC ID: PMC7899671
Article link: Elife
Grant support: [+]

GO keywords: neurotransmitter-gated ion channel clustering

Article Images: [+] show captions
References [+] :
Agarwal, Patterns in Outpatient Benzodiazepine Prescribing in the United States. 2019, Pubmed