RESEARCH ARTICLE Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist Stephanie E Crilly1,2, Wooree Ko2†, Zara Y Weinberg2‡, Manojkumar A Puthenveedu1,2* 1Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States; 2Department of Pharmacology University of Michigan Medical School, Ann Arbor, United States Abstract The prevailing model for the variety in drug responses is that different drugs stabilize distinct active states of their G protein-coupled receptor (GPCR) targets, allowing coupling to different effectors. However, whether the same ligand generates different GPCR active states based on the immediate environment of receptors is not known. Here we address this question using spatially resolved imaging of conformational biosensors that read out distinct active *For correspondence: conformations of the d-opioid receptor (DOR), a physiologically relevant GPCR localized to Golgi
[email protected] and the surface in neuronal cells. We have shown that Golgi and surface pools of DOR both inhibit Present address: †Department cAMP, but engage distinct conformational biosensors in response to the same ligand in rat of Pharmacology and Physiology, neuroendocrine cells. Further, DOR recruits arrestins on the surface but not on the Golgi. Our University of Rochester Medical results suggest that the local environment determines the active states of receptors for any given Center, Rochester, United drug, allowing GPCRs to couple to different effectors at different subcellular locations. States; ‡Department of Biochemistry and Biophysics, California Institute for Quantitative Biosciences, Introduction University of California, San A given G protein-coupled receptor (GPCR) can generate a diverse array of signaling responses, Francisco, San Francisco, United States underscoring the physiological and clinical relevance of this class of proteins.