A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action.
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.
['Stoeber|Miriam|M|', 'Jullié|Damien|D|', 'Lobingier|Braden T|BT|', 'Laeremans|Toon|T|', 'Steyaert|Jan|J|', 'Schiller|Peter W|PW|', 'Manglik|Aashish|A|', 'von Zastrow|Mark|M|']
D000701:Analgesics, Opioid D000818:Animals D015374:Biosensing Techniques D002462:Cell Membrane D003712:Dendrites D011992:Endosomes D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- D020881:Enkephalin, D-Penicillamine (2,5)- D016308:Enkephalin, Leucine-2-Alanine D006056:Golgi Apparatus D057809:HEK293 Cells D006367:HeLa Cells D006801:Humans D042541:Intracellular Space D008856:Microscopy, Fluorescence D009020:Morphine D009270:Naloxone D009292:Narcotic Antagonists D009474:Neurons D010455:Peptides D051381:Rats D011957:Receptors, Opioid D062211:Spatio-Temporal Analysis
biosensor opioid drug opioid receptor subcellular location ligand-induced activation endosome Golgi GPCR ligand bias signaling