δ-opioid receptor activation leads to neurite outgrowth and neuronal differentiation via a STAT5B-Gαi/o pathway

Authors

  • Eirini-Maria Georganta,

    1. Laboratory of Cellular Signalling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Athens, Greece
    Current affiliation:
    1. Biomedical Sciences Research Center ‘Alexander Fleming,’, 16672, Vari, Greece
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  • Lambrini Tsoutsi,

    1. Laboratory of Cellular Signalling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Athens, Greece
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  • Maria Gaitanou,

    1. Laboratory of Cellular and Molecular Neurobiology, Hellenic Pasteur Institute, Athens, Greece
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  • Zafiroula Georgoussi

    Corresponding author
    1. Laboratory of Cellular Signalling and Molecular Pharmacology, Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Athens, Greece
    • Address correspondence and reprint requests to Zafiroula Georgoussi, N.C.S.R. “Demokritos”, Laboratory of Cellular Signaling and Molecular Pharmacology, Institute of Biosciences and Applications, 15310 Ag. Paraskevi-Attikis, Athens, Greece. E-mail: iro@bio.demokritos.gr

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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-Ser2, Leu5, Thr6]-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.

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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.

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