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Agonist-Specific Regulation of Parathyroid Hormone (PTH) Receptor Type 2 Activity: Structural and Functional Analysis of PTH- and Tuberoinfundibular Peptide (TIP) 39-Stimulated Desensitization and Internalization

Division of Endocrinology and Metabolism (A.B.), Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Division of Bone Diseases (D.M., D.D.P., R.R., S.L.F.), Department of Rehabilitation and Geriatrics, Geneva University Hospital, 1211 Geneva, Switzerland; and Laboratory of Genetics (T.B.U.), National Institute of Mental Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Serge L. Ferrari, Division of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail: serge.ferrari{at}medecine.unige.ch.

The human PTH receptor type 2 (PTH2R) is activated by PTH and tuberoinfundibular peptide of 39 residues (TIP39), resulting in cAMP and intracellular Ca signaling. We now report that, despite these similarities, PTH and TIP39 elicit distinct responses from PTH2R. First, TIP39 induced ß-arrestin and protein kinase Cß mobilization and receptor internalization, whereas PTH did not. However, PTH stimulated trafficking of these molecules for a chimeric PTH2R containing the N terminus and third extracellular loop of PTH receptor type 1 (PTH1R). Second, whereas PTH-stimulated cAMP activity was brief and rapidly resensitized, the response to TIP39 was sustained and partly desensitized for a prolonged period. PTH2R desensitization was mediated by ß-arrestin interaction with the C terminus (amino acids 426–457) of PTH2R, whereas ß-arrestin mobilization had a minor influence on PTH2R internalization in response to TIP39, as shown with C terminus deletion mutants and/or dominant negative forms of ß-arrestin and dynamin. These data contrast with PTH1R, at which these dominant negative mutants markedly inhibited receptor internalization. Collectively, these results further highlight how specific interactions within the ligand-receptor bimolecular complex mediate distinct postactivation responses of class II G protein- coupled receptors and provide novel insights into the physiological regulation of PTH2R activity.

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