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This version published online on March 11, 2004
Endocrinology, doi:10.1210/en.2003-1185
A more recent version of this article appeared on June 1, 2004
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Submitted on September 9, 2003
Accepted on March 4, 2004

Ligand-selective Dissociation of Activation and Internalization of the Parathyroid Hormone Receptor. Conditional efficacy of PTH peptide fragments

W. BRUCE SNEDDON, CLARA E. MAGYAR, GORDON E. WILLICK, COLIN A. SYME, FERRUCCIO GALBIATI, ALESSANDRO BISELLO, and PETER A. FRIEDMAN*

Departments of Pharmacology (W.B.S., C.E.M., F.G., P.A.F.) and of Medicine (C.A.S., A.B., P.A.F.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and Institute for Biological Sciences, National Research Council (G.E.W), Ottawa, Ontario, Canada K1A 0R6

* To whom correspondence should be addressed. E-mail: paf10{at}pitt.edu.

G protein-coupled receptors (GPCRs) mediate the action of many hormones, cytokines, sensory, and chemical signals. It is generally thought that receptor desensitization and internalization require occupancy and activation of the GPCR. The parathyroid hormone (PTH) and PTH-related peptide receptor (PTH1R) belongs to GPCR class B and is the major regulator of extracellular calcium homeostasis. Using kidney distal convoluted tubule (DCT) cells transfected with a human PTH1R/EGFP fusion protein, quantitative, real-time fluorescence microscopy was used to analyze receptor internalization. In these cells, which are the target of the calcium-sparing action of PTH, PTH(1-34) activated adenylyl cyclase (AC) and phospholipase C (PLC) and PTH1R endocytosis. PTH(1-31), however, stimulated AC and PLC, but not PTH1R endocytosis. Conversely, PTH(7-34) rapidly stimulated PTH1R internalization without activating AC or PLC. PTH(2-34) and 3-34 caused PTH1R internalization intermediate between PTH(1-34) and 7-34. PTH1R sequestration occurred in a dynamin- and clathrin-dependent manner. Directly activating AC inhibited PTH1R internalization in response to PTH(7-34). PTH1R endocytosis was sensitive to PKC inhibition. PTH(1-34), 7-34, and 1-31 evoked PTH1R phosphorylation. Removal of most of the C-terminus of the PTH1R eliminated receptor phosphorylation and the cAMP/PKC sensitivity of internalization. PTH(1-34) and 7-34 internalized the truncated PTH1R with identical kinetics and the response was unaffected by forskolin. Thus, the PTH1R C-terminus contains regulatory sequences that are involved in, but not required for PTH1R internalization. The results demonstrate that receptor activation and internalization can be selectively dissociated.
Key words: G protein-coupled receptors • receptor internalization • signal transduction • cell-specific signaling




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