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This version published online on February 26, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0487
Molecular Endocrinology Vol. 0, No. 2004 200304871-
doi:10.1210/me.2003-0487
Copyright © 2004 by the Endocrine Society.
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Submitted on December 18, 2003
Accepted on February 18, 2004

Agonist-specific Regulation of Parathyroid Hormone Receptor Type 2 Activity. Structural and Functional Analysis of PTH- and TIP39-stimulated Desensitization and Internalization

Alessandro Bisello, Danielle Manen, Dominique D. Pierroz, Ted B. Usdin, René Rizzoli, and Serge L. Ferrari*

Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261; Division of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospital, 1211Geneva, Switzerland; Laboratory of Genetics, NIMH, Bethesda, MD 20892.

* To whom correspondence should be addressed. E-mail: serge.ferrari{at}medecine.unige.ch.

The human parathyroid hormone (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 {beta}-arrestin and PKC{beta} 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, while 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 {beta}-arrestin interaction with the C-terminus (amino acids 426-457) of PTH2R, whereas {beta}-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 {beta}-arrestin2 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 post-activation responses of Class II GPCRs and provide novel insights into the physiological regulation of PTH2R activity.
Key words: GPCR • PTH/PTHrP receptor • PTH2 receptor • TIP39 • {beta}-arrestin • PKC • signaling • internalization




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