Author:

Keywords:

Science & Technology, Physical Sciences, Chemistry, Multidisciplinary, Chemistry, PROTEIN-COUPLED RECEPTORS, STRUCTURAL REQUIREMENTS, PHOTOCHROMIC AGONIST, EXTRACELLULAR LOOP, GLUTAMATE-RECEPTOR, BETA-ARRESTIN, BINDING-SITE, D-1 RECEPTOR, D2 RECEPTOR, MECHANISMS, Binding Sites, Cysteine, Dopamine, Dopamine D2 Receptor Antagonists, Drug Inverse Agonism, Humans, Ligands, Receptors, Dopamine D1, Receptors, Dopamine D2, 03 Chemical Sciences, General Chemistry, 34 Chemical sciences, 40 Engineering

Abstract:

Family A G protein-coupled receptors (GPCRs) control diverse biological processes and are of great clinical relevance. Their archetype rhodopsin becomes naturally light sensitive by binding covalently to the photoswitchable tethered ligand (PTL) retinal. Other GPCRs, however, neither bind covalently to ligands nor are light sensitive. We sought to impart the logic of rhodopsin to light-insensitive Family A GPCRs in order to enable their remote control in a receptorspecific, cell-type-specific and spatio-temporally precise manner. Dopamine receptors (DARs) are of particular interest for their roles in motor coordination, appetitive and aversive behavior, as well as neuropsychiatric disorders such as Parkinson’s disease, schizophrenia, mood disorders and addiction. Using an azobenzene derivative of the well-known DAR ligand PPHT, we were able to rapidly, reversibly and selectively block dopamine D1 and D2 receptor (D1R and D2R) when the PTL was conjugated to an engineered cysteine near the dopamine binding site. Depending on the site of tethering, the ligand behaved as either a photoswitchable tethered neutral antagonist (PTNA) or inverse agonist (PTIA). Our results indicate that DARs can be chemically engineered for selective remote control by light and provide a template for precision control of Family A GPCRs.