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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.

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