HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 50, 36214-36222, December 14, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/50/36214    most recent M707263200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, B. Articles by Friedman, P. A. Search for Related Content PubMed PubMed Citation Articles by Wang, B. Articles by Friedman, P. A. Social Bookmarking                      What's this?

NHERF1 Regulates Parathyroid Hormone Receptor Membrane Retention without Affecting Recycling^*

From the Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Na/H exchange regulatory factor-1 (NHERF1) is a PDZ protein that regulates trafficking of several G protein-coupled receptors. The phenotype of NHERF1-null mice suggests that the parathyroid hormone (PTH) receptor (PTH1R) is the principal GPCR interacting with NHERF1. The effect of NHERF1 on receptor recycling is unknown. Here, we characterized NHERF1 effects on PTH1R membrane tethering and recycling by radio-ligand binding and recovery after maximal receptor endocytosis. Using Chinese hamster ovary cells expressing the PTH1R, where NHERF1 expression could be induced by tetracycline, NHERF1 inhibited PTH1R endocytosis and delayed PTH1R recycling. NHERF1 also inhibited PTH-induced receptor internalization in MC4 osteoblast cells. Reducing constitutive NHERF1 levels in HEK-293 cells with short hairpin RNA directed against NHERF1 augmented PTH1R endocytosis in response to PTH. Mutagenesis of the PDZ-binding domains or deletion of the MERM domain of NHERF1 demonstrated that both are required for inhibition of endocytosis and recycling. Likewise, an intact COOH-terminal PDZ recognition motif in PTH1R is needed. The effect of NHERF1 on receptor internalization and recycling was not associated with altered receptor expression or binding, activation, or phosphorylation but involved β-arrestin and dynamin. We conclude that NHERF1 inhibits endocytosis without affecting PTH1R recycling in MC4 and PTH1R-expressing HEK-293 cells. Such an effect may protect against PTH resistance or PTH1R down-regulation in certain cells harboring NHERF1.

Received for publication, August 29, 2007 , and in revised form, September 19, 2007.

^* This work was supported by National Institutes of Health Grants DK-54171 and DK-69998 (to P. A. F.) and an internal grant from the Office of the Senior Vice Chancellor for the Health Sciences, University of Pittsburgh (to G. G. R.). 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 To whom correspondence should be addressed: Dept. of Pharmacology, University of Pittsburgh School of Medicine, E-1347 Biomedical Science Tower, Pittsburgh, PA 15261. Tel.: 412-383-7783; Fax: 412-648-1945; E-mail: paf10{at}pitt.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. Wang, Y. Yang, A. B. Abou-Samra, and P. A. Friedman NHERF1 Regulates Parathyroid Hormone Receptor Desensitization: Interference with {beta}-Arrestin Binding Mol. Pharmacol., May 1, 2009; 75(5): 1189 - 1197. [Abstract] [Full Text] [PDF]

				P. J. Baugher and A. Richmond The Carboxyl-terminal PDZ Ligand Motif of Chemokine Receptor CXCR2 Modulates Post-endocytic Sorting and Cellular Chemotaxis J. Biol. Chem., November 7, 2008; 283(45): 30868 - 30878. [Abstract] [Full Text] [PDF]

				C. N. A. Bezerra, A. C. C. Girardi, L. R. Carraro-Lacroix, and N. A. Reboucas Mechanisms underlying the long-term regulation of NHE3 by parathyroid hormone Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1232 - F1237. [Abstract] [Full Text] [PDF]

				B. Wang, Y. Yang, and P. A. Friedman Na/H Exchange Regulatory Factor 1, a Novel AKT-associating Protein, Regulates Extracellular Signal-regulated Kinase Signaling through a B-Raf-Mediated Pathway Mol. Biol. Cell, April 1, 2008; 19(4): 1637 - 1645. [Abstract] [Full Text] [PDF]