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Inhibition of the biosynthesis of the human endothelin B receptor by the cyclodepsipeptide cotransin

Item Type:Article
Title:Inhibition of the biosynthesis of the human endothelin B receptor by the cyclodepsipeptide cotransin
Creators Name:Westendorf, C. and Schmidt, A. and Coin, I. and Furkert, J. and Ridelis, I. and Zampatis, D. and Rutz, C. and Wiesner, B. and Rosenthal, W. and Beyermann, M. and Schuelein, R.
Abstract:The specific inhibition of the biosynthesis of target proteins is a relatively novel strategy in pharmacology and is based mainly on antisense approaches (e.g. antisense oligonucleotides or RNA interference). Recently, a novel class of substances was described acting at a later step of protein biosynthesis. The cyclic heptadepsipeptides CAM741 and cotransin were shown to inhibit selectively the biosynthesis of a small subset of secretory proteins by preventing stable insertion of the nascent chains into the Sec61 translocon complex at the endoplasmic reticulum membrane (Besemer et al., Nature 436, 290f, 2005; Garrison et al., Nature 436, 285f, 2005). These peptides act in a signal sequence-discriminatory manner which explains their selectivity. Here we have analyzed the cotransin sensitivity of various G protein-coupled receptors (GPCRs) in transfected HEK 293 cells. We show that the biosynthesis of the human endothelin B receptor (ETBR) is highly sensitive to cotransin, in contrast to that of the other GPCRs analyzed. Using a novel biosynthesis assay based on fusions with the photoconvertible Kaede protein, we show that the IC50 value of cotransin action on ETBR biosynthesis is 5.4 uM and that ETBR signalling could be completely blocked by treating cells with 30 uM of cotransin. Taken together, our data add an integral membrane protein, namely the ETBR, to the small group of cotransin-sensitive proteins.
Keywords:G Protein Coupled Receptors (GPCR), Protein Export, Protein Translocation, Receptor Regulation, Receptors
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:35588-35600
Date:14 October 2011
Official Publication:https://doi.org/10.1074/jbc.M111.239244
PubMed:View item in PubMed

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