Single-molecule visualization of human A_2A adenosine receptor activation by a G protein and constitutively activating mutations.

ABSTRACT: Mutations that constitutively activate G protein-coupled receptors (GPCRs), known as constitutively activating mutations (CAMs), modify cell signaling and interfere with drugs, resulting in diseases with limited treatment options. We utilize fluorescence imaging at the single-molecule level to visualize the dynamic process of CAM-mediated activation of the human A_2A adenosine receptor (A_2AAR) in real time. We observe an active-state population for all CAMs without agonist stimulation. Importantly, activating mutations significantly increase the population of an intermediate state crucial for receptor activation, notably distinct from the addition of a partner G protein. Activation kinetics show that while CAMs increase the frequency of transitions to the intermediate

SUBMITTER: Wei S 

PROVIDER: S-EPMC10689853 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature