μ‐Opioid Agonist Inhibition of κ‐Opioid Receptor‐Stimulated Extracellular Signal‐Regulated Kinase Phosphorylation Is Dynamin‐Dependent in C6 Glioma Cells

Open Access
Publisher Website
Google Scholar
Abstract
In previous studies we found that μ‐opioids, acting via μ‐opioid receptors, inhibit endothelin‐stimulated C6 glioma cell growth. In the preceding article we show that the κ‐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 μ‐opioid agonists for 1 h results in the inhibition of κ‐opioid mitogenic signaling. The μ‐selective agonist endomorphin‐1 attenuates κ‐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 κ‐opioid phosphorylation of extracellular signal‐regulated kinase. However, it does block the inhibitory action on κ‐opioid signaling mediated by the κ‐opioid receptor. Our results are consistent with a growing body of evidence of the opposing actions of μ‐ and κ‐opioids and provide new insight into the role of opioid receptor trafficking in signaling.