PT  - JOURNAL ARTICLE
AU  - Alken, Martina
AU  - Schmidt, Antje
AU  - Rutz, Claudia
AU  - Furkert, Jens
AU  - Kleinau, Gunnar
AU  - Rosenthal, Walter
AU  - Schülein, Ralf
TI  - The Sequence after the Signal Peptide of the G Protein-Coupled Endothelin B Receptor Is Required for Efficient Translocon Gating at the Endoplasmic Reticulum Membrane
AID  - 10.1124/mol.108.051581
DP  - 2009 Apr 01
TA  - Molecular Pharmacology
PG  - 801--811
VI  - 75
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/75/4/801.short
4100  - http://molpharm.aspetjournals.org/content/75/4/801.full
SO  - Mol Pharmacol2009 Apr 01; 75
AB  - The heptahelical G protein-coupled receptors (GPCRs) must reach their correct subcellular location to exert their function. Receptor domains relevant for receptor trafficking include signal sequences mediating receptor integration into the membrane of the endoplasmic reticulum (ER) and anterograde or retrograde transport signals promoting receptor sorting into the vesicles of the secretory pathway. In addition, receptors must be correctly folded to pass the quality control system of the early secretory pathway. Taking the endothelin B receptor as a model, we describe a new type of a transport-relevant GPCR domain. Deletion of this domain (residues Glu28 to Trp54) leads to a fully functional receptor protein that is expressed at a lower level than the wild-type receptor. Subcellular localization experiments and glycosylation state analyses demonstrate that the mutant receptor is neither misfolded, retained intracellularly, nor misrouted. Fluorescence recovery after photobleaching analyses demonstrate that constitutive internalization is also not affected. By using an in vitro prion protein targeting assay, we show that this domain is necessary for efficient translocon gating at the ER membrane during early receptor biogenesis. Taken together, we identified a novel transport-relevant domain in the GPCR protein family. Our data may also be relevant for other GPCRs and unrelated integral membrane proteins. The American Society for Pharmacology and Experimental Therapeutics