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

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Abstract

Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that modulate activity of GABA_A receptors (GABA_ARs), 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'Tb₂g_2L) 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.

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

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Joseph W Nors

Neuroscience, University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Shipra Gupta

Neuroscience, University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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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.