Distinct loops in arrestin differentially regulateligand binding within the GPCR opsin

摘要

G-protein-coupled receptors are universally regulated by arrestin binding. Here we showthat rod arrestin induces uptake of the agonist all-trans-retinol in only half the population ofphosphorylated opsin in the native membrane. Agonist uptake blocks subsequent entry ofthe inverse agonist 11-cis-retinal (that is, regeneration of rhodopsin), but regeneration is notblocked in the other half of aporeceptors. Environmentally sensitive fluorophores attachedto arrestin reported that conformational changes in loopV-VI (n-domain) are coupled to the entry of agonist, while loopXVIII-XIX (C-domain) engages the aporeceptor even before agonist is added. The data are most consistent with a model in which each domain of arrestin engages its own aporeceptor, and the different binding preferences of the domains lead toasymmetric ligand binding by the aporeceptors. such a mechanism would protect the rod cellin bright light by concurrently sequestering toxic all-trans-retinol and allowing regenerationwith 11-cis-retinal.