[delta]-opioid receptor activation leads to neurite outgrowth and neuronal differentiation via a STAT5B-G[alpha]i/o pathway

• Published in: Journal of neurochemistry Vol. 127; no. 3; p. 329
• Main Authors: Georganta, Eirini-Maria, Tsoutsi, Lambrini, Gaitanou, Maria, Georgoussi, Zafiroula
• Format: Journal Article
• Language: English
• Published: New York Blackwell Publishing Ltd 01.11.2013
• Subjects: Brain; Gene expression; Neurochemistry; Neurons; Signal transduction
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12386

It remains unclear how opioid receptors ([delta], µ, [kappa]) 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 [delta]-opioid receptor ([delta]-OR) activation with opioid agonists induces STAT5B phosphorylation in Neuro-2A cells. Moreover, [D-Ser2, Leu5, Thr6]-enkephalin-activation of [delta]-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-Ser2, Leu5, Thr6]-enkephalin exposure of neuroblastoma cells induces a marked increase in the differentiation marker proteins, [beta]III-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 [delta]-OR activation leads to a number of neurotropic events via a G[alpha]i/o-linked and STAT5B-dependent manner. We propose a novel signalling pathway for [delta]-opioid receptor ([delta]-ΟR)-mediated neurotropic events. STAT5B interacts with the [delta]-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 [delta]-OR activation and suggest a possible neuroprotective role opioids could exert. [PUBLICATION ABSTRACT]