Essential Site Maintenance: Authorea-powered sites will be updated circa 15:00-17:00 Eastern on Tuesday 5 November.
There should be no interruption to normal services, but please contact us at [email protected] in case you face any issues.

loading page

The role of κ-opioid receptor-induced autophagy in stress-driven synaptic alterations
  • +4
  • Christos Karoussiotis,
  • Aggeliki Sotiriou,
  • Alexia Polissidis,
  • Alexandra Symeonof,
  • Danai Papavranoussi-Daponte,
  • Vassiliki Nikoletopoulou,
  • Zafiroula Georgoussi
Christos Karoussiotis
National Centre for Scientific Research-Demokritos

Corresponding Author:[email protected]

Author Profile
Aggeliki Sotiriou
IMBB
Author Profile
Alexia Polissidis
Biomedical Research Foundation of the Academy of Athens
Author Profile
Alexandra Symeonof
National Centre for Scientific Research-Demokritos
Author Profile
Danai Papavranoussi-Daponte
National Centre for Scientific Research-Demokritos
Author Profile
Vassiliki Nikoletopoulou
University of Lausanne Faculty of Biology and Medicine
Author Profile
Zafiroula Georgoussi
National Centre for Scientific Research-Demokritos
Author Profile

Abstract

Recent evidence has shown that G protein-coupled receptors (GPCRs) are direct sensors of the autophagic machinery and οpioid receptors regulate neuronal plasticity and neurotransmission with an as yet unclarified mechanism. Using in vitro and in vivo experimental approaches, this study aims to clarify the potential role of autophagy and κ-opioid receptor (κ-OR) signaling on synaptic structure and integrity. We hereby demonstrate that the selective κ-OR agonist U50,488H, induces autophagy in a time-and dose-dependent manner in neuronal cells by upregulating microtubule-associated protein Light Chain 3-II (LC3-II), Beclin 1 and Autophagy Related Gene 5 (ATG5). Pretreatment of neuronal cells with pertussis toxin blocked the above κ-OR-mediated cellular responses. 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 in the hippocampus with a concomitant decrease of several pre- and post-synaptic proteins such as spinophilin, postsynaptic density protein 95 (PSD-95) and synaptosomal associated protein 25 (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-binaltorphimine (norBNI), 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 signaling regulates brain plasticity.