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Distinct Regulation of Internalization and Mitogen-Activated Protein Kinase Activation by Two Isoforms of the Dopamine D2 Receptor

School of Life Sciences and Biotechnology (S.J.K., M.Y.K., E.J.L., J.-H.B.), Korea University, Seoul 136-701, South Korea; and Brain Korea 21 Project for Medical Science (S.J.K., E.J.L.) and Department of Pharmacology (Y.S.A.), College of Medicine, Yonsei University, Seoul 120-752, South Korea

Address all correspondence and requests for reprints to: Dr. Ja-Hyun Baik, Molecular Neurobiology Laboratory, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea. E-mail: jahyunb{at}korea.ac.kr.

Two isoforms of the dopamine D2 receptor, D2L (long) and D2S (short), differ by the insertion of a 29-amino acid specific to D2L within the putative third intracellular loop of the receptor. Here, we examined D2 receptor-mediated MAPK activation in association with receptor internalization. Overexpression of ß-arrestin 1 and 2 increased the D2S-mediated activation of MAPK, whereas it did not affect the activation of MAPK by D2L. Expression of a dominant negative ß-arrestin 2 (319–418) mutant and of a dominant negative dynamin I (K44A) mutant inhibited the activation of MAPK by D2S, but not the activation of MAPK by D2L. Treatment with inhibitors of internalization, i.e. concanavalin A and monodansylcadaverin, blocked D2S-mediated MAPK activation but not D2L-mediated activation. By confocal microscopy, we observed ß-arrestin 1 and 2, translocated to the plasma membrane and colocalized with D2L and D2S receptors upon stimulation with dopamine, and this was followed by the translocation of receptors into endocytic vesicles. Moreover, the expression of the ß-arrestin 2 (319–418) mutant blocked the internalization of both D2L and D2S. In addition, although K44A dynamin mutant expression did not alter D2L internalization, it completely blocked the internalization of D2S. The stimulation of D2L induces activation of MAPK via transactivation of the platelet-derived growth factor receptor, whereas D2S does not. Taken together, these data suggest that D2L activates MAPK signaling by mobilizing the growth factor receptor, platelet-derived growth factor receptor, whereas D2S appears to activate MAPK signaling by mobilizing clathrin-mediated endocytosis in a ß-arrestin/dynamin-dependent manner.

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