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Parathyroid hormone acts as a pharmacological chaperone on the parathyroid hormone receptor
Author(s) -
Klenk Christoph,
Lohse Martin J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.726.10
Subject(s) - parathyroid hormone receptor , parathyroid hormone , receptor , chemistry , endoplasmic reticulum , microbiology and biotechnology , g protein coupled receptor , internalization , endocrinology , medicine , hormone receptor , biology , biochemistry , calcium , organic chemistry , cancer , breast cancer
Parathyroid hormone receptor (PTH1R) belongs to class B G‐protein‐coupled receptors and is the major regulator of extracellular calcium homeostasis. Binding of the native ligand parathyroid hormone (PTH) or biologically active peptide fragments of PTH to the receptor lead to the activation of Gs and Gq/G11 pathways with subsequent stimulation of adenylyl cyclase and phospholipase C. Activation of the PTH1R is followed by the recruitment of beta‐arrestin and subsequently to an efficient internalization of the receptor from the cell surface within several minutes. Here we show that long‐term stimulation of the PTH1R over several hours with PTH resulted in increased cellular protein levels and enhanced membrane distribution of the receptor. This increase of receptor levels was accompanied by an accumulation of high molecular mass moieties of the PTH1R. Analysis of the maturation steps during biosynthesis of the PTH1R revealed that the increased molecular mass was caused by a differential glycosylation pattern of the receptor. Blocking the export from the endoplasmic reticulum of the newly synthesized receptor by Brefeldin A completely inhibited the PTH induced mass changes. We therefore propose a ligand‐mediated stabilization of immature receptors in the endoplasmic reticulum which could eventually lead to a more efficient maturation of the PTH1R.