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Megalin antagonizes activation of the parathyroid hormone receptor

Item Type:Article
Title:Megalin antagonizes activation of the parathyroid hormone receptor
Creators Name:Hilpert, J. and Nykjaer, A. and Jacobsen, C. and Wallukat, G. and Nielsen, R. and Moestrup, S.K. and Haller, H. and Luft, F.C. and Christensen, E.I. and Willnow, T.E.
Abstract:Parathyroid hormone (PTH) is predominantly cleared from the circulation by glomerular filtration and degradation in the renal proximal tubules. Here, we demonstrate that megalin, a multifunctional endocytic receptor in the proximal tubular epithelium, mediates the uptake and degradation of PTH. Megalin was purified from kidney membranes as the major PTH-binding protein and shown in BIAcore analysis to specifically bind full-length PTH and amino-terminal PTH fragments (Kd 0.5 microM). Absence of the receptor in megalin knockout mice resulted in 4-fold increased levels of amino-terminal PTH fragments in the urine. In F9 cells expressing both megalin and the PTH/PTH-related peptide receptor (PTH/PTHrP receptor), uptake and lysosomal degradation of the hormone was mediated through megalin. Blocking megalin-mediated clearance of PTH resulted in 3-fold increased stimulation of the PTH/PTHrP receptor. These data provide evidence that megalin is involved in the renal catabolism of PTH and potentially antagonizes PTH/PTHrP receptor activity in the proximal tubular epithelium.
Keywords:Base Sequence, Cattle, Cultured Tumor Cells, DNA Primers, Heymann Nephritis Antigenic Complex, Immunohistochemistry, Kidney, Membrane Glycoproteins, Molecular Cloning, Parathyroid Hormone, Parathyroid Hormone Receptors, Animals, Mice, Rats
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:274
Number:9
Page Range:5620-5625
Date:26 February 1999
Official Publication:http://www.jbc.org/cgi/content/abstract/274/9/5620
PubMed:View item in PubMed

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