Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

• Published in: eLife Vol. 10
• Main Authors: Liu, Lei, Fan, Zhiran, Rovira, Xavier, Xue, Li, Roux, Salomé, Brabet, Isabelle, Xin, Mingxia, Pin, Jean-Philippe, Rondard, Philippe, Liu, Jianfeng
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 06.12.2021; eLife Sciences Publications Ltd; eLife Sciences Publication; eLife Sciences Publications, Ltd
• Subjects: allosteric agonism; allosteric modulator; Allosteric properties; Allosteric Regulation; Binding sites; Biochemistry and Chemical Biology; Experiments; G protein; G protein-coupled receptors; G proteins; GABA-B; HEK293 Cells; Humans; Life Sciences; Ligands; metabotropic glutamate receptor; Mutation; Neurons and Cognition; oligomer; Pharmaceutical sciences; Pharmacology; Physiological aspects; Physiology; Protein Domains; Proteins; Receptors, GABA-B - genetics; Receptors, GABA-B - metabolism; Scientific equipment and supplies industry; Signal transduction; Site-directed mutagenesis; Therapeutic targets; Transmembrane domains; γ-Aminobutyric acid B receptors; United States; allosteric agonism; chemical biology; GABA-B; metabotropic glutamate receptor; biochemistry; oligomer; human; G protein; allosteric modulator
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.70188

G protein-coupled receptors (GPCRs) are among the most promising drug targets. They often form homo- and heterodimers with allosteric cross-talk between receptor entities, which contributes to fine-tuning of transmembrane signaling. Specifically controlling the activity of GPCR dimers with ligands is a good approach to clarify their physiological roles and validate them as drug targets. Here, we examined the mode of action of positive allosteric modulators (PAMs) that bind at the interface of the transmembrane domains of the heterodimeric GABA receptor. Our site-directed mutagenesis results show that mutations of this interface impact the function of the three PAMs tested. The data support the inference that they act at the active interface between both transmembrane domains, the binding site involving residues of the TM6s of the GABA and the GABA subunit. Importantly, the agonist activity of these PAMs involves a key region in the central core of the GABA transmembrane domain, which also controls the constitutive activity of the GABA receptor. This region corresponds to the sodium ion binding site in class A GPCRs that controls the basal state of the receptors. Overall, these data reveal the possibility of developing allosteric compounds able to specifically modulate the activity of GPCR homo- and heterodimers by acting at their transmembrane interface.