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J Neurochem ; 127(3): 329-41, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23906478

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, ßIII-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.


Subject(s)
GTP-Binding Protein alpha Subunits, Gi-Go/drug effects , Neurons/drug effects , Receptors, Opioid, delta/metabolism , STAT5 Transcription Factor/physiology , Signal Transduction/drug effects , Animals , Blotting, Western , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Survival/physiology , Enkephalins/metabolism , Fluorescent Antibody Technique , Humans , Immunoprecipitation , Mice , Neurites/drug effects , Neurogenesis/physiology , Phosphorylation , Receptors, Opioid, delta/drug effects
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