(691.3) Autophagy Induction Via κ-Opioid Receptor is Implicated in Stress-Driven Synaptic Alterations

Poster Board Number: B11

Zafiroula Georgoussi (National Centre for Scientific Research "Demokritos", Institute of Biosciences and Applications, Athens, Greece), Christos Karoussiotis (National Centre for Scientific Research "Demokritos", Institute of Biosciences and Applications), Aggeliki Sotiriou (Foundation for Research and Technology, Crete, Greece), Alexia Polissidis (Biomedical Research Foundation of the Academy of Athens, Athens, Greece), Danae Papavranoussi-Daponte (National Centre for Scientific Research "Demokritos", Institute of Biosciences and Applications), Alexandra Symeonof (National Centre for Scientific Research "Demokritos", Institute of Biosciences and Applications), Vassiliki Nikoletopoulou (University of Lausanne, Faculty of Biology and Medicine, Switzerland.)

Neuronal autophagy controls the quality of cytoplasmic proteins through degradation of important synaptic proteins and modulates synaptic organization and morphogenesis (1). Evidence has shown that G protein coupled receptors are direct sensors regulating the autophagic machinery (2) and opioid receptors regulate neuronal plasticity and neurotransmission with as yet unclarified mechanism (3,4). Using in vitro and in vivo studies, we demonstrated that κ-opioid receptor (κ-OR) agonists induce autophagy via a PTX-sensitive G protein manner and identified the downstream components involved (5). Our molecular analysis also revealed a κ-OR-driven upregulation of becn1 gene through ERK1,2-dependent activation of the transcription factor CREB in neuronal cells. Moreover, our studies demonstrated that sub-chronic U50,488H administration in mice causes profound increases of specific autophagic markers exclusively in the hippocampus with a concomitant decrease of several pre- and post-synaptic proteins such as spinophilin, PSD-95 and SNAP25. Finally, using acute stress, a stimulus known to increase the levels of the endogenous κ-OR ligand dynorphin, we are demonstrating that administration of the κ-ΟR selective antagonist, nor-binaltorhimine, blocks the induction of autophagy and the stress-evoked reduction of synaptic proteins in the hippocampus. These findings provide novel insights about the essential role of autophagic machinery into the mechanisms through which κ-OR and its signaling regulates brain plasticity.

References

1.  Nikoletopoulou V, Papandreou ME, Tavernarakis N (2015)  Cell Death Differ 22: 398-407

2. Wauson EM, Dbouk HA, Ghosh AB, Cobb MH (2014) Trends Endocrinol Metab 25: 274-2823.

3.Georganta EM, Tsoutsi L, Gaitanou M, Georgoussi Z (2013) J Neurochem 127: 329-341

4. Kibaly C, Xu C, Cahill CM, Evans CJ, Law PY (2019)  Nat Rev Neurosci 20: 5-18

5. Georgoussi Z and Karoussiotis C (2019) FASEB J.  Supplement Issue Vol.33

This work was supported by the GSRT Excellence II 3722 - "NO-LGOS" - to Z.G; the SANITURA (MIS 5002514) grant, implemented under the Action for the Strategic Development on the Research and Technological Sectors amp;amp; the OPENSCREEN-GR amp;ldquo;An Open-Access Research Infrastructure of Chemical Biology and Target-Based Screening Technologies for Human and Animal Health, Agriculture and the Environmentamp;rdquo; (MIS 5002691) funded by the Operational Programme "Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020).