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J. Biol. Chem., Vol. 278, Issue 44, 43787-43796, October 31, 2003

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Activation-independent Parathyroid Hormone Receptor Internalization Is Regulated by NHERF1 (EBP50)^*

W. Bruce Sneddon, Colin A. Syme, Alessandro Bisello, Clara E. Magyar||||, Moulay Driss Rochdi¶||, Jean-Luc Parent¶, Edward J. Weinman**, Abdul B. Abou-Samra, and Peter A. Friedman¶¶

From the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, the Department of Medicine, Division of Endocrinology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, the ^¶Rheumatology Division, Faculty of Medicine and Clinical Research Centre, University of Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada, the ^**Departments of Medicine and Physiology, University of Maryland School of Medicine, and Department of Veterans Affairs Medical Center, Baltimore, Maryland 21201, the Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and the Department of Medicine, Renal Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Parathyroid hormone (PTH) regulates extracellular calcium homeostasis through the type 1 PTH receptor (PTH1R) expressed in kidney and bone. The PTH1R undergoes -arrestin/dynamin-mediated endocytosis in response to the biologically active forms of PTH, PTH-(1–34), and PTH-(1–84). We now show that amino-truncated forms of PTH that do not activate the PTH1R nonetheless induce PTH1R internalization in a cell-specific pattern. Activation-independent PTH1R endocytosis proceeds through a distinct arrestin-independent mechanism that is operative in cells lacking the adaptor protein Na/H exchange regulatory factor 1 (NHERF1) (ezrin-binding protein 50). Using a combination of radioligand binding experiments and quantitative, live cell confocal microscopy of fluorescently tagged PTH1Rs, we show that in kidney distal tubule cells and rat osteosarcoma cells, which lack NHERF1, the synthetic antagonist PTH-(7–34) and naturally circulating PTH-(7–84) induce internalization of PTH1R in a -arrestin-independent but dynamin-dependent manner. Expression of NHERF1 in these cells inhibited antagonist-induced endocytosis. Conversely, expression of dominant-negative forms of NHERF1 conferred internalization sensitivity to PTH-(7–34) in cells expressing NHERF1. Mutation of the PTH1R PDZ-binding motif abrogated interaction of the receptor with NHERF1. These mutated receptors were fully functional but were now internalized in response to PTH-(7–34) even in NHERF1-expressing cells. Removing the NHERF1 ERM domain or inhibiting actin polymerization allowed otherwise inactive ligands to internalize the PTH1R. These results demonstrate that NHERF1 acts as a molecular switch that legislates the conditional efficacy of PTH fragments. Distinct endocytic pathways are determined by NHERF1 that are operative for the PTH1R in kidney and bone cells.

Received for publication, June 9, 2003 , and in revised form, August 13, 2003.

^* This work was supported in part by National Institutes of Health (NIH) Grants DK-54171 (to P. A. F.) and DK-62078 (to A. B.) and the Canadian Institutes of Health Research (CIHR) and the Kidney Foundation of Canada (J-L. P.). 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.

^|||| Supported in part by NIH Training Grant DK54171.

^|| Recipient of a CIHR doctoral award.

^¶¶ To whom correspondence should be addressed: University of Pittsburgh School of Medicine, Dept. of Pharmacology, E-1347 Biomedical Science Tower, Pittsburgh, PA 15261. Tel.: 412-383-7783; Fax: 412-648-1945; E-mail: paf10{at}pitt.edu.

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