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J. Biol. Chem., Vol. 281, Issue 16, 10856-10864, April 21, 2006

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Distinct -Arrestin- and G Protein-dependent Pathways for Parathyroid Hormone Receptor-stimulated ERK1/2 Activation^*

Diane Gesty-Palmer, Minyong Chen, Eric Reiter^¶, Seungkirl Ahn, Christopher D. Nelson, Shuntai Wang^||, Allen E. Eckhardt^||, Conrad L. Cowan^||, Robert F. Spurney, Louis M. Luttrell^**, and Robert J. Lefkowitz¹

From the Departments of Medicine and Biochemistry, Howard Hughes Medical Institute, Duke University, Medical Center, Durham, North Carolina 27710, the Geriatrics Research, Education and Clinical Center, Durham Veterans Affairs Medical Center, Durham, North Carolina 27705, the ^¶Institut National de la Recherche Agronomique, 37380 Nouzilly, France, the ^||Xsira Pharmaceuticals, Morrisville, North Carolina 27709, the ^**Departments of Medicine and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, and the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401

Parathyroid hormone (PTH) regulates calcium homeostasis via the type I PTH/PTH-related peptide (PTH/PTHrP) receptor (PTH1R). The purpose of the present study was to identify the contributions of distinct signaling mechanisms to PTH-stimulated activation of the mitogen-activated protein kinases (MAPK) ERK1/2. In Human embryonic kidney 293 (HEK293) cells transiently transfected with hPTH1R, PTH stimulated a robust increase in ERK activity. The time course of ERK1/2 activation was biphasic with an early peak at 10 min and a later sustained ERK1/2 activation persisting for greater than 60 min. Pretreatment of HEK293 cells with the PKA inhibitor H89 or the PKC inhibitor GF109203X, individually or in combination reduced the early component of PTH-stimulated ERK activity. However, these inhibitors of second messenger dependent kinases had little effect on the later phase of PTH-stimulated ERK1/2 phosphorylation. This later phase of ERK1/2 activation at 30–60 min was blocked by depletion of cellular -arrestin 2 and -arrestin 1 by small interfering RNA. Furthermore, stimulation of hPTH1R with PTH analogues, [Trp¹]PTHrp-(1–36) and [D-Trp¹²,Tyr³⁴]PTH-(7–34), selectively activated G_s/PKA-mediated ERK1/2 activation or G protein-independent/-arrestin-dependent ERK1/2 activation, respectively. It is concluded that PTH stimulates ERK1/2 through several distinct signal transduction pathways: an early G protein-dependent pathway meditated by PKA and PKC and a late pathway independent of G proteins mediated through -arrestins. These findings imply the existence of distinct active conformations of the hPTH1R responsible for the two pathways, which can be stimulated by unique ligands. Such ligands may have distinct and valuable therapeutic properties.

Received for publication, December 15, 2005 , and in revised form, February 13, 2006.

^* This work was supported by National Institutes of Health Grants HL16037, HL70631, DK64353, and HD043446. 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.

¹ Investigator with the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Inst., Duke University Medical Center, Box 3821, Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: lefko001{at}receptor-biol.duke.edu.

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