Mu-opioid agonist inhibition of kappa-opioid receptor-stimulated extracellular signal-regulated kinase phosphorylation is dynamin-dependent in C6 glioma cells.
In previous studies we found that mu-opioids, acting via mu-opioid receptors, inhibit endothelin-stimulated C6 glioma cell growth. In the preceding article we show that the kappa-selective opioid agonist U69,593 acts as a mitogen with a potency similar to that of endothelin in the same astrocytic model system. Here we report that C6 cell treatment with mu-opioid agonists for 1 h results in the inhibition of kappa-opioid mitogenic signaling. The mu-selective agonist endomorphin-1 attenuates kappa-opioid-stimulated DNA synthesis, phosphoinositide turnover, and extracellular signal-regulated kinase phosphorylation. To investigate the role of receptor endocytosis in signaling, we have examined the effects of dynamin-1 and its GTPase-defective, dominant suppressor mutant (K44A) on opioid modulation of extracellular signal-regulated kinase phosphorylation in C6 cells. Overexpression of dynamin K44A in C6 cells does not affect kappa-opioid phosphorylation of extracellular signal-regulated kinase. However, it does block the inhibitory action on kappa-opioid signaling mediated by the kappa-opioid receptor. Our results are consistent with a growing body of evidence of the opposing actions of mu- and kappa-opioids and provide new insight into the role of opioid receptor trafficking in signaling.
Bohn
L M
LM
E.A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, Missouri 63104, USA.
Belcheva
M M
MM
Coscia
C J
CJ
D000818:Animals; D044482:Benzeneacetamides; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D034284:Dynamin I; D034281:Dynamins; D016232:Endothelins / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000502:physiology*; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000502:physiology; D014407:Tumor Cells, Cultured
D044482:Benzeneacetamides; D016232:Endothelins; D009842:Oligopeptides; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C105294:endomorphin 2; D009020:Morphine; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D034284:Dynamin I; D020558:GTP Phosphohydrolases; D034281:Dynamins; C045444:U 69593