Dual mechanisms of cholesterol-GPCR interactions that depend on membrane phospholipid composition.

ABSTRACT: Cholesterol is a critical component of mammalian cell membranes and an allosteric modulator of G protein-coupled receptors (GPCRs), but divergent views exist on the mechanisms by which cholesterol influences receptor functions. Leveraging the benefits of lipid nanodiscs, i.e., quantitative control of lipid composition, we observe distinct impacts of cholesterol in the presence and absence of anionic phospholipids on the function-related conformational dynamics of the human A_2A adenosine receptor (A_2AAR). Direct receptor-cholesterol interactions drive activation of agonist-bound A_2AAR in membranes containing zwitterionic phospholipids. Intriguingly, the presence of anionic lipids attenuates cholesterol's impact through direct interactions with the receptor,

SUBMITTER: Ray AP 

PROVIDER: S-EPMC10330489 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature