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Regulation of G‐Protein Coupled Receptor Traffic by an Evolutionary Conserved Hydrophobic Signal
Author(s) -
Angelotti Tim,
Daunt David,
Shcherbakova Olga G.,
Kobilka Brian,
Hurt Carl M.
Publication year - 2010
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2010.01033.x
Subject(s) - g protein coupled receptor , er retention , biology , endoplasmic reticulum , microbiology and biotechnology , receptor , extracellular , heterologous expression , conserved sequence , transport protein , signal peptide , signal transduction , membrane protein , biochemistry , peptide sequence , membrane , gene , recombinant dna , mutant
Plasma membrane (PM) expression of G‐protein coupled receptors (GPCRs) is required for activation by extracellular ligands; however, mechanisms that regulate PM expression of GPCRs are poorly understood. For some GPCRs, such as alpha2c‐adrenergic receptors (α 2c ‐ARs), heterologous expression in non‐native cells results in limited PM expression and extensive endoplasmic reticulum (ER) retention. Recently, ER export/retentions signals have been proposed to regulate cellular trafficking of several GPCRs. By utilizing a chimeric α 2a /α 2c ‐AR strategy, we identified an evolutionary conserved hydrophobic sequence (ALAAAL) in the extracellular amino terminal region that is responsible in part for α 2c ‐AR subtype‐specific trafficking. To our knowledge, this is the first luminal ER retention signal reported for a GPCR. Removal or disruption of the ER retention signal dramatically increased PM expression and decreased ER retention. Conversely, transplantation of this hydrophobic sequence into α 2a ‐ARs reduced their PM expression and increased ER retention. This evolutionary conserved hydrophobic trafficking signal within α 2c ‐ARs serves as a regulator of GPCR trafficking.