Megalin antagonizes activation of the parathyroid hormone receptor

Citation
J. Hilpert et al., Megalin antagonizes activation of the parathyroid hormone receptor, J BIOL CHEM, 274(9), 1999, pp. 5620-5625
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
274
Issue
9
Year of publication
1999
Pages
5620 - 5625
Database
ISI
SICI code
0021-9258(19990226)274:9<5620:MAAOTP>2.0.ZU;2-4
Abstract
Parathyroid hormone(PTH) is predominantly cleared from the circulation by g lomerular filtration and degradation in the renal proximal tubules. Here, w e demonstrate that megalin, a multifunctional endocytic receptor in the pro ximal tubular epithelium, mediates the uptake and degradation of PTH. Megal in was purified from kidney membranes as the major PTH-binding protein and shown in BIAcore analysis to specifically bind full-length PTH and amino-te rminal PTH fragments (K-d 0.5 mu M) Absence of the receptor in megalin knoc kout mice resulted in 4-fold increased levels of amino-terminal PTH fragmen ts in the urine, In F9 cells expressing both megalin and the PTH/PTH-relate d peptide receptor (PTH/PTHrP receptor), uptake and lysosomal degradation o f the hormone was mediated through megalin. Blocking megalin-mediated clear ance of PTH resulted in 3-fold increased stimulation of the PTH/PTRrP recep tor. These data provide evidence that megalin is involved in the renal cata bolism of PTH and potentially antagonizes PTH/PTHrP receptor activity in th e proximal tubular epithelium.