This Article Full Text Full Text (PDF) Alert me when this article is cited 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 Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sneddon, W. B. Articles by Friedman, P. A. Search for Related Content PubMed PubMed Citation Articles by Sneddon, W. B. Articles by Friedman, P. A.

ß-Arrestin-Dependent Parathyroid Hormone-Stimulated Extracellular Signal-Regulated Kinase Activation and Parathyroid Hormone Type 1 Receptor Internalization

Departments of Pharmacology (W.B.S., P.A.F.), and Medicine (P.A.F.), Renal Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Address all correspondence and requests for reprints to: Peter A. Friedman, Ph.D., Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261. E-mail: paf10{at}pitt.edu.

PTH regulates renal calcium homeostasis by actions on the distal nephron. PTH-induced calcium transport in mouse distal convoluted tubule (DCT) cells requires activation of ERK1/2. ERK activation by ß-adrenergic receptors occurs in a biphasic manner and involves receptor internalization. An early rapid phase is ß-arrestin (ßAr) independent, whereas prolonged activation is ßAr dependent. We characterized PTH-stimulated ERK activation and the involvement of receptor internalization and ßAr dependence. In DCT cells, PTH transiently activated ERK maximally at 5 min and then returned to baseline. ßAr dependence of PTH receptor (PTH1R)-mediated ERK stimulation was assessed using mouse embryonic fibroblasts (MEFs) from ßAr1- and -2-null mice. In wild-type MEFs, PTH(1–34)-stimulated ERK activation peaked after 5 min, was 50% maximal after 15 min, and then recovered to 80% of maximal stimulation by 30 min. In MEFs null for ßAr1 and -2, PTH-stimulated ERK activation peaked by 5 min and returned to baseline. The effect was identical in ßAr2-null MEFs. In ßAr1-null MEFs, ERK exhibited delayed activation and remained elevated. PTH-stimulated ERK activation and receptor endocytosis were not inhibited by the clathrin-binding domain of ßAr1 [Ar(319–418)]. Coexpression of the sodium proton exchanger regulatory factor 1 (NHERF1) with Ar(319–418) blocked PTH1R internalization. We conclude that PTH-stimulated ERK activation in DCT cells proceeds with a rapid but transient phase that may involve ßAr1. Furthermore, the ßAr-dependent late phase of ERK activation by PTH requires the participation of ßAr2 and PTH1R internalization.

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]

				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]

				B. Wang, A. Bisello, Y. Yang, G. G. Romero, and P. A. Friedman NHERF1 Regulates Parathyroid Hormone Receptor Membrane Retention without Affecting Recycling J. Biol. Chem., December 14, 2007; 282(50): 36214 - 36222. [Abstract] [Full Text] [PDF]