4.8 Article

Conformational specificity of opioid receptors is determined by subcellular location irrespective of agonist

Journal

ELIFE
Volume 10, Issue -, Pages -

Publisher

ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.67478

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Funding

  1. National Science Foundation [DGE 1256260, 1935926]
  2. National Institute of General Medical Sciences [GM117425]
  3. Direct For Biological Sciences [1935926] Funding Source: National Science Foundation
  4. Div Of Molecular and Cellular Bioscience [1935926] Funding Source: National Science Foundation

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The study reveals that the same ligand can activate different active states of G protein-coupled receptors (GPCRs) in distinct cellular environments, allowing for coupling to different effectors. By investigating Golgi and surface pools, researchers can understand the receptor's different responses to drugs in different subcellular locations.
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 conformations of the delta-opioid receptor (DOR), a physiologically relevant GPCR localized to Golgi and the surface in neuronal cells. We have shown that Golgi and surface pools of DOR both inhibit cAMP, but engage distinct conformational biosensors in response to the same ligand in rat neuroendocrine cells. Further, DOR recruits arrestins on the surface but not on the Golgi. Our results suggest that the local environment determines the active states of receptors for any given drug, allowing GPCRs to couple to different effectors at different subcellular locations.

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