κ‐Opioid Receptor Activation Induces the Autophagic Machinery and Alters Dendritic Spine Density

Abstract

It is already evident that opioid receptors modulate the neuronal function by regulating neurite outgrowth and neurotransmission with unknown yet mechanisms (1, 2). Autophagy is a lysosomal degradation pathway which eliminates misfolded proteins and dysfunctional organelles essential for neuronal function and homeostasis (3). Recent observations have shown that G‐protein coupled receptors could mediate the autophagic machinery and that methamphetamine induces autophagy in endothelial cells through the κ‐OR (4). However, it is unknown whether specific κ‐opioid agonists mediate these effects and whether opiodergic alterations in neuronal cells could be controlled through induction of autophagy. Our data indicate that administration of κ‐selective agonists increase the levels of the autophagosome marker LC3‐II (Fig. 1) and the pre‐autophagosomal proteins Beclin 1 and ATG5 respectively in a dose and time dependent manner. These effects are reversed upon exposure of neuroblastoma cells and cortical neurons with the opioid receptor antagonist naloxone, suggesting that it is a κ‐OR‐mediated effect. Pre‐treatment of cells with pertussis toxin blocked the κ‐OR mediated Beclin 1 upregulation and LC3‐II formation, suggesting that Gi/Go proteins are involved in κ‐OR induced autophagy. Futhermore, κ‐opioid agonist exposure of primary neuronal cortical cultures decreased the levels of Neurabin II, a neuronal protein enriched in dendritic spines, and the levels of Synaptophysin, a synaptic terminal protein, suggesting that these proteins are engulfed in the κ‐OR mediated autophagic cargo. Collectively, the present results demonstrate a novel regulatory mechanism via which specifιc κ‐OR agonists affect dendritic spine morphology via induction of autophagy.Support or Funding InformationThis work was supported mainly by the GSRT Excellence II grant, 3722 entitled “Neurite Outrgowth: ALternative G‐ protein coupled Opioid receptor Signaling”‐ “NO‐ALGOS” to Z.G. We acknowledge support of this work also by the project “Target Identification and Development of Novel Approaches for Health and Environmental Applications” (MIS 5002514) which is implemented under the Action for the Strategic Development on the Research and Technological Sectors, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co‐financed by Greece and the European Union (European Regional Development Fund). The facilities of the Hellenic Research Infrastructure OPENSCREEN‐GR were used.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.