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A genetically encoded biosensor reveals location bias of opioid drug action

Jullié, Damien
Lobingier, Braden T
Laeremans, Toon
Steyaert, Jan
Schiller, Peter W
Manglik, Aashish
von Zastrow, Mark
Published in Neuron. 2018, vol. 98, no. 5, p. 963-976.e5
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.
Keywords AnalgesicsOpioid/metabolismAnimalsBiosensing TechniquesCell Membrane/metabolismDendrites/metabolismEndosomes/metabolismEnkephalinAla2 MePhe4 Gly5/metabolismEnkephalinD Penicillamine 2.5/metabolismEnkephalinLeucine2Alanine/metabolismGolgi Apparatus/metabolismHEK293 CellsHeLa CellsHumansIntracellular SpaceMicroscopyFluorescenceMorphine/metabolismNaloxoneNarcotic AntagonistsNeurons/metabolismPeptides/metabolismRatsReceptorsOpioid/metabolismSpatio Temporal Analysis
PMID: 29754753
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Article (Published version) (6.3 MB) - public document Free access
Research group Contrôle subcellulaire des récepteurs de signalisation (1005)
Swiss National Science Foundation: P2EZP3_152173
Swiss National Science Foundation: P300PA_164712
(ISO format)
STOEBER, Miriam Carolin et al. A genetically encoded biosensor reveals location bias of opioid drug action. In: Neuron, 2018, vol. 98, n° 5, p. 963-976.e5. doi: 10.1016/j.neuron.2018.04.021

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Deposited on : 2019-09-12

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