Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.12.12.520050v1?rss=1

Authors: Radoux-Mergault, A., Oberhauser, L., Aureli, S., Gervasio, F. L., Stoeber, M.

Abstract:
G protein-coupled receptors in intracellular organelles can be activated in response to membrane permeant ligands, which contributes to the diversity and specificity of agonist action. The opioid receptors (ORs) provide a striking example, where opioid drugs activate ORs in the Golgi apparatus within seconds of drug addition. Till date, our knowledge on the signaling of intracellular GPCRs remains incomplete and it is unknown if the downstream effects triggered by ORs in plasma membrane and Golgi apparatus differ. To address this gap, we first assess the recruitment of signal transducers to ORs in both compartments. We find that Golgi-localized ORs couple to Gai/o probes and are phosphorylated by GPCR kinases (GRK2/3), but unlike plasma membrane receptors, do not recruit b-arrestin or a specific Ga probe. Subsequent molecular dynamics simulations with OR-transducer complexes in model bilayers mimicking plasma membrane or Golgi composition reveal that the lipid environment promotes location selective coupling. Unbiased global analyses then show that OR activation in the plasma membrane and Golgi apparatus has strikingly different downstream effects on transcription and protein phosphorylation. Taken together, the study delineates OR signal transduction with unprecedented spatial resolution and reveals that the subcellular location defines the signaling effect of opioid drugs.

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