Work

Cholesterol differentially modulates the activity of opioid and muscarinic receptors via a common binding site

Year: 2025

Type: article

Abstract: G protein-coupled receptors (GPCRs) are membrane proteins that represent the largest and most therapeutically targeted receptor class, accounting for 30% of currently marketed drugs. Two binding motifs for membrane cholesterol, the cholesterol recognition amino acid consensus (CRAC) domain and the cholesterol consensus motif (CCM), have been postulated. Using a simulation of the molecular dynamics of cholesterol association with the receptor, we predicted the binding of membrane cholesterol to non-canonical sites, distinct from CRAC and CCM, at muscarinic and opioid receptors. We identified a binding site common to muscarinic and opioid receptors at TM6, with arginine 6.35 as the major residue. Membrane cholesterol depletion mimics the effects of R 6.35 mutations, confirming its role in receptor modulation. Targeting cholesterol-binding sites offers novel pharmacotherapeutic strategies, including tissue-specific sterol-based modulation. One sentence summary This study identifies a shared non-canonical cholesterol-binding site at TM6 in muscarinic and opioid receptors, with significant implications for drug development targeting tissue-specific GPCR modulation.

Source: Biochemical Pharmacology

DOI: 10.1016/j.bcp.2025.117296

Authors: Nikolai Chetverikov, Alena Janoušková-Randáková, Dominik Nelic, Jan Jakubík

Institutions: Czech Academy of Sciences, Institute of Physiology, Czech Academy of Sciences

Language: English

Topic: Receptor Mechanisms and Signaling

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,590