Structural Basis for the Allosteric Modulation of the GABAA Receptors by Diazepam

Overview

The GABAA receptor (GABAAR), a pentameric ligand-gated ion channel, is activated by GABA, an endogenous inhibitory neurotransmitter in the human brain. GABAAR dysfunction is implicated in several central nervous system disorders, including anxiety, depression, and epilepsy. Drugs such as benzodiazepines, which positively allosterically modulate GABAAR, have been used extensively to treat such diseases despite many side effects, including tolerance, withdrawal, and potential for abuse. Two neurosteroids, allopregnanolone and ganaxolone, were recently approved by the US FDA to treat epilepsy and depression, and these drugs seem to show higher efficacy and fewer unintended side effects. Recent advances in structural biology yielded multiple cryo-EM structures of GABAAR bound to various allosteric modulators providing valuable insights into their mechanism of action. However, the mechanistic details of how these allosteric modulators affect GABAAR (in open, closed, and desensitized functional states) remain poorly understood. In this study, long-timescale classical molecular dynamics simulations were used to investigate the underlying mechanism of diazepam (DZP, benzodiazepine) action and compared it with that of ganaxolone (GNX, neurosteroid). Specifically, the effects of the ligands on the stability and binding interactions of GABA at the orthosteric sites, global conformational changes, and changes in the pore characteristics and dimensions were investigated. The obtained results indicate that diazepam and ganaxolone have distinct allosteric mechanisms. Specifically, GNX facilitates recovery of the receptor from its desensitized state by promoting GABA dissociation, whereas DZP appears to strengthen the GABA’s affinity for the receptors in a state-independent manner. These results provide valuable insights into the fundamental mechanisms of these widely used drugs and will facilitate the design of new drugs with higher efficacy and better safety profiles.

Competition history

• AJAS 2024 Category not listed

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