Residues and residue pairs of evolutionary importance differentially direct signaling bias of D2 dopamine receptors

摘要: The D2 dopamine receptor and the serotonin 5-hydroxytryptamine 2A (5-HT2A) are closely-related G-protein-coupled receptors (GPCRs) from class A bioamine subfamily. Despite structural similarity, they respond to distinct ligands through downstream pathways, whose dysregulation is linked depression, bipolar disorder, addiction, psychosis. They important drug targets, it understand how their bias toward G-protein versus β-arrestin signaling pathways regulated. Previously, evolution-based computational approaches, difference Evolutionary Trace Trace-Mutual information (ET-Mip), revealed residues residue pairs that, when switched in corresponding 5-HT2A, altered ligand potency activation efficiency. We have tested these swaps for ability trigger recruitment of β-arrestin2 response or serotonin. results reveal that selected modulate agonist potency, maximal efficacy, constitutive activity recruitment. Whereas most variants was similar WT lower than activation, N124H3.42 more 5-fold higher. T205M5.54 displayed high activity, enhanced efficacy relative WT, L379F6.41 virtually inactive. These striking differences were largely reversed by a compensating mutation (T205M5.54/L379F6.41) at previously identified ET-Mip as functionally coupled. observation signs magnitudes effects mutations several cases odds with on suggests also bias.