Roles of hydrophilic residues in GABA binding site of GABA-ρ1 receptor explain the addition/inhibition effects of competitive ligands.

The orthosteric binding site of GABA-gated ion channels has been widely explored. Many residues in the binding site of GABA were studied. The interactions due to the binding of GABA into the binding site drive channel activation and determine the potency and efficacy of GABA response. The combined effect of a competitive ligand and GABA on GABA-ρ1 receptors has been poorly studied. Here, we used point mutations, molecular modeling, and electrophysiological studies to explore the role of two hydrophilic residues (Serine 168 and Serine 243) of the GABA-ρ1 receptors in response to the binding of GABA and other studied ligands. Our results suggested that Ser168 residue stabilizes either closed state or open conformation depending on the other determinant interactions of each state. On the other hand, Ser243 residue is predicted to form different inter-subunit interactions with residues in the adjacent subunit at different states of the channel. Our current findings enlighten us to reasonably explain the additive/inhibitive effects of applying a competitive ligand with GABA simultaneously. Understanding the mixed effect of potentiation and inhibition would facilitate the discovery of new drugs to work as a direct GABA's activity modulators with more selectivity at various subunits forming GABA-gated ion channels.

Informations de copyright

Copyright © 2021. Published by Elsevier Ltd.