Abstract
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 a1M2-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 (a1L9'Tb2g2L) directly activated by BZDs. We identify a specific residue whose mutation (a1V279A) 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.
Article and author information
Author details
Funding
University of Texas at Austin (Department of Neuroscience Startup)
- Marcel P Goldschen-Ohm
University of Texas at Austin (STARS)
- Marcel P Goldschen-Ohm
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Leon D Islas, Universidad Nacional Autónoma de México, Mexico
Publication history
- Received: October 27, 2020
- Accepted: February 15, 2021
- Accepted Manuscript published: February 16, 2021 (version 1)
- Version of Record published: February 22, 2021 (version 2)
Copyright
© 2021, Nors et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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