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

  1. Joseph W Nors
  2. Shipra Gupta
  3. Marcel P Goldschen-Ohm  Is a corresponding author
  1. University of Texas at Austin, United States

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.

Data availability

Source code for the modeling depicted in Figure 9 has been provided.

Article and author information

Author details

  1. Joseph W Nors

    Neuroscience, University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shipra Gupta

    Neuroscience, University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Marcel P Goldschen-Ohm

    Neuroscience, University of Texas at Austin, Austin, United States
    For correspondence
    marcel.goldschen-ohm@austin.utexas.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1466-9808

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

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Publication history

  1. Received: October 27, 2020
  2. Accepted: February 15, 2021
  3. Accepted Manuscript published: February 16, 2021 (version 1)
  4. 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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  1. Joseph W Nors
  2. Shipra Gupta
  3. Marcel P Goldschen-Ohm
(2021)
A critical residue in the α1M2-M3 linker regulating mammalian GABAA receptor pore gating by diazepam
eLife 10:e64400.
https://doi.org/10.7554/eLife.64400

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