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J. Biol. Chem., Vol. 280, Issue 9, 7808-7816, March 4, 2005

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Internalization and Src Activity Regulate the Time Course of ERK Activation by Delta Opioid Receptor Ligands^*

Nicolas Audet, Mélanie Paquin-Gobeil, Olivier Landry-Paquet¶, Peter W. Schiller||, and Graciela Piñeyro**

From the Département de Pharmacologie, the ^¶Département de Biochimie, and the ^**Département de Psychiatrie, Faculté de Médecine and the ^||Institut des Recherches Cliniques de Montréal, Université de Montréal, Montréal, Quebec H1N3V2, Canada

The present study showed that delta opioid receptor (OR) ligands Tyr-Ticpsi [CH₂-NH]Cha-Phe-OH (TICP) and ICI174864 behaved as inverse agonists in the cyclase pathway but induced agonist responses in the ERK cascade. Unlike ligands that behaved as agonists in both pathways, and whose stimulation of ERK was marked but transient (10 min), ERK activation by ICI174864 and TICP was moderate and sustained, lasting for more than 1 h in the case of TICP. Biochemical experiments showed that duration of ERK activation by agonists and "dual efficacy ligands" was inversely correlated with their ability to trigger receptor phosphorylation and degradation. Thus, although TICP stabilized ORs in a conformation that did not incorporate ³²P, was not a substrate for tyrosine kinase Src, and was not down-regulated following prolonged exposure to the drug, the conformation stabilized by D-Pen-2,5-enkephalin (DPDPE) incorporated ³²P, was phosphorylated by Src, and suffered degradation within the first 2 h of treatment. Inhibition of endocytosis by sucrose prolonged ERK activation by DPDPE increasing the decay half-life of the response to values that resembled those of dual efficacy ligands (from a 2-min decay t increased to 12 min). Src inhibitor PP2 also prolonged ERK stimulation by DPDPE. It did so by maintaining a sustained activation of the kinase at 20% of maximum following an initial rapid reduction in the response. These results show that specific kinetics of ERK activation by agonists and dual efficacy ligands are determined, at least in part, by the differential ability of the two types of drugs to trigger mechanisms regulating OR responsiveness.

Received for publication, October 14, 2004 , and in revised form, December 2, 2004.

^* This work was supported in part by Grant MOP-57910 from the Canadian Institutes of Health Research and a grant from Fonds de Recherche en Santé de Québec (FRSQ). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Holds a studentship from FRSQ.

Recipient of a fellowship for young researchers from FRSQ. To whom correspondence should be addressed: Dépt. de Psychiatrie, Université de Montréal, 7331 Rue Hochelaga, Montréal, Qc H1N3V2, Canada. Tel.: 514-251-4015; Fax: 514-251-2617; E-mail: graciela.pineyro{at}crfs.umontreal.ca.

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