A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action

Miriam Stoeber, Damien Jullié, Braden T. Lobingier, Toon Laeremans, Jan Steyaert, Peter W. Schiller, Aashish Manglik, Mark von Zastrow

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Opioid receptors (ORs) precisely modulate behavior when activated by native peptide ligands but distort behaviors to produce pathology when activated by non-peptide drugs. A fundamental question is how drugs differ from peptides in their actions on target neurons. Here, we show that drugs differ in the subcellular location at which they activate ORs. We develop a genetically encoded biosensor that directly detects ligand-induced activation of ORs and uncover a real-time map of the spatiotemporal organization of OR activation in living neurons. Peptide agonists produce a characteristic activation pattern initiated in the plasma membrane and propagating to endosomes after receptor internalization. Drugs produce a different activation pattern by additionally driving OR activation in the somatic Golgi apparatus and Golgi elements extending throughout the dendritic arbor. These results establish an approach to probe the cellular basis of neuromodulation and reveal that drugs distort the spatiotemporal landscape of neuronal OR activation. Opioid drugs and endogenous peptide neuromodulators exert their biological effects through opioid receptors. Stoeber et al. develop a sensor that detects opioid receptor activation in neurons with subcellular resolution and find that peptides and drugs drive different spatiotemporal activation patterns.

Original languageEnglish (US)
Pages (from-to)963-976.e5
JournalNeuron
Volume98
Issue number5
DOIs
StatePublished - Jun 6 2018
Externally publishedYes

Keywords

  • GPCR
  • Golgi
  • biosensor
  • endosome
  • ligand bias
  • ligand-induced activation
  • opioid drug
  • opioid receptor
  • signaling
  • subcellular location

ASJC Scopus subject areas

  • Neuroscience(all)

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