Kappa opioid receptor endocytosis by dynorphin peptides.

Abstract

Internalization and downregulation are important steps in the modulation of receptor function. Recent work with the beta2 adrenergic and opioid receptors have implicated these processes in receptor-mediated activation of mitogen-activated protein kinase (MAPK). We have used CHO cells expressing epitope-tagged rat kappa opioid receptors (rKORs) and prodynorphin-derived peptides to characterize the agonist-mediated endocytosis of rKORs and activation of MAPK. Kappa receptor-selective peptides induced receptor internalization and downregulation whereas nonpeptide agonists did not. An examination of the ability of dynorphin A-17-related peptides (lacking C-terminal amino acids) to promote KOR internalization, inhibition of adenylyl cyclase, and MAPK phosphorylation revealed that the N-terminal seven residues play an important role in eliciting these responses. Both dynorphin peptides and nonpeptide agonists induced rapid and robust phosphorylation of MAPKs. Taken together, these results point to a difference in the ability of dynorphin peptides and nonpeptide ligands to promote rKOR endocytosis and support the view that rKOR internalization is not required for MAPK activation.