The role of κ-opioid receptor-induced autophagy in stress-driven
synaptic alterations
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.