title: δ-opioid receptor activation leads to neurite outgrowth and neuronal differentiation via a STAT5B-Gαi/o pathway.
abstract: It remains unclear how opioid receptors (δ, μ, κ) are implicated in mechanisms controlling differentiation, cell proliferation, and survival. Opioid receptors are coupled to Gi/Go proteins and recent findings have shown that opioid receptors can form a multicomponent signaling complex, consisting of members of G protein and the signal transducer and activator of transcription (STAT)5B. We thus wondered whether activation of the opioid receptors could direct differentiation and neurite outgrowth through a molecular pathway involving STAT5B and other signaling intermediates. We demonstrate that prolonged δ-opioid receptor (δ-OR) activation with opioid agonists induces STAT5B phosphorylation in Neuro-2A cells. Moreover, [D-Ser2, Leu5, Thr6]-enkephalin-activation of δ-OR triggers neurite outgrowth and neuronal survival; these effects are blocked by the selective antagonist naltrindole, by treatment with pertussis toxin, and after expression of a dominant negative mutant of STAT5B (DN-STAT5B), suggesting that the signaling pathway participating in this mechanism involves Gi/o proteins and p-STAT5B. Additional studies have shown that while [D-Ser(2) , Leu(5) , Thr(6) ]-enkephalin exposure of neuroblastoma cells induces a marked increase in the differentiation marker proteins, βIII-tubulin (Tuj-1), synaptophysin, and neural cell adhesion molecule, over-expression of the DN-STAT5B attenuated significantly their expression levels. Taken together, our findings demonstrate that δ-OR activation leads to a number of neurotropic events via a Gαi/o-linked and STAT5B-dependent manner. We propose a novel signalling pathway for δ-opioid receptor (δ-ΟR)-mediated neurotropic events. STAT5B interacts with the δ-ΟR and upon prolonged receptor activation phosphorylates STAT5B in a Gi/Go dependent manner leading to increased neuronal survival, neurite outgrowth and differentiation. These findings contribute to a better understanding of the molecular and cellular events following δ-OR activation and suggest a possible neuroprotective role opioids could exert.
authors.affiliation: Laboratory of Cellular Signalling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, Greece.
authors.forename: Eirini-Maria
authors.initials: EM
authors.lastname: Georganta
authors.forename: Lambrini
authors.initials: L
authors.lastname: Tsoutsi
authors.forename: Maria
authors.initials: M
authors.lastname: Gaitanou
authors.forename: Zafiroula
authors.initials: Z
authors.lastname: Georgoussi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004745:Enkephalins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D016501:Neurites / Q000187:drug effects; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D010766:Phosphorylation; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D004745:Enkephalins; D017465:Receptors, Opioid, delta; D050799:STAT5 Transcription Factor; C494096:Stat5b protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
keywords: Gα subunits; differentiation; neurite outgrowth; neuronal survival; signal transducer and activator of transcription 5B; δ-opioid receptor