PMID- 36466809
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221206
IS  - 1662-5099 (Print)
IS  - 1662-5099 (Electronic)
IS  - 1662-5099 (Linking)
VI  - 15
DP  - 2022
TI  - The kappa-opioid receptor-induced autophagy is implicated in stress-driven synaptic 
      alterations.
PG  - 1039135
LID - 10.3389/fnmol.2022.1039135 [doi]
LID - 1039135
AB  - Recent evidence has shown that G protein-coupled receptors (GPCRs) are direct 
      sensors of the autophagic machinery and opioid 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 kappa-opioid receptor (kappa-OR) signaling in synaptic 
      alterations. We hereby demonstrate that the selective kappa-OR agonist U50,488H, 
      induces autophagy in a time-and dose-dependent manner in Neuro-2A cells stably 
      expressing the human kappa-OR 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 kappa-OR-mediated cellular 
      responses. Our molecular analysis also revealed a kappa-OR-driven upregulation of 
      becn1 gene through ERK1,2-dependent activation of the transcription factor CREB 
      in Neuro-2A 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 kappa-OR ligand dynorphin, we 
      are demonstrating that administration of the kappa-OmicronR 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 kappa-OR signaling regulates brain plasticity.
CI  - Copyright (c) 2022 Karoussiotis, Sotiriou, Polissidis, Symeonof, 
      Papavranoussi-Daponte, Nikoletopoulou and Georgoussi.
FAU - Karoussiotis, Christos
AU  - Karoussiotis C
AD  - Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of 
      Biosciences and Applications, National Centre for Scientific Research 
      "Demokritos", Athens, Greece.
FAU - Sotiriou, Aggeliki
AU  - Sotiriou A
AD  - Institute of Molecular Biology and Biotechnology, Foundation for Research and 
      Technology-Hellas, Heraklion, Crete, Greece.
FAU - Polissidis, Alexia
AU  - Polissidis A
AD  - Center for Clinical Research, Experimental Surgery, and Translational Research, 
      Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
FAU - Symeonof, Alexandra
AU  - Symeonof A
AD  - Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of 
      Biosciences and Applications, National Centre for Scientific Research 
      "Demokritos", Athens, Greece.
FAU - Papavranoussi-Daponte, Danae
AU  - Papavranoussi-Daponte D
AD  - Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of 
      Biosciences and Applications, National Centre for Scientific Research 
      "Demokritos", Athens, Greece.
FAU - Nikoletopoulou, Vassiliki
AU  - Nikoletopoulou V
AD  - Departement des Neurosciences Fondamentales, University of Lausanne, Lausanne, 
      Switzerland.
FAU - Georgoussi, Zafiroula
AU  - Georgoussi Z
AD  - Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of 
      Biosciences and Applications, National Centre for Scientific Research 
      "Demokritos", Athens, Greece.
LA  - eng
PT  - Journal Article
DEP - 20221116
PL  - Switzerland
TA  - Front Mol Neurosci
JT  - Frontiers in molecular neuroscience
JID - 101477914
PMC - PMC9709411
OTO - NOTNLM
OT  - Beclin 1
OT  - CREB
OT  - ERK1,2
OT  - Gi/o
OT  - autophagy
OT  - dynorphin
OT  - synaptic alterations
OT  - kappa-opioid receptor
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/12/06 06:00
MHDA- 2022/12/06 06:01
PMCR- 2022/01/01
CRDT- 2022/12/05 04:11
PHST- 2022/09/07 00:00 [received]
PHST- 2022/10/26 00:00 [accepted]
PHST- 2022/12/05 04:11 [entrez]
PHST- 2022/12/06 06:00 [pubmed]
PHST- 2022/12/06 06:01 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fnmol.2022.1039135 [doi]
PST - epublish
SO  - Front Mol Neurosci. 2022 Nov 16;15:1039135. doi: 10.3389/fnmol.2022.1039135. 
      eCollection 2022.