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Evolutionarily conserved trafficking signal within the alpha2c adrenergic receptor restricts plasma membrane expression

Plasma membrane (PM) expression of polytopic cargo proteins such as, G‐protein coupled receptors (GPCRs) is required for their activation by extracellular ligands. For some GPCRs such as, the alpha2c‐adrenergic receptor (α2c‐AR), their heterologous expression results in limited PM expression and intracellular (IC) retention in the endoplasmic reticulum (ER). To date, the structural determinants within the α2c‐AR that dictate its trafficking have yet to be elucidated. Utilizing a chimeric α2a‐/α2c‐AR strategy, we were able to localize the region responsible for α2c‐AR peculiar trafficking to an evolutionary conserved hydrophobic sequence within the extracellular amino terminus. Deletion of this trafficking signal in the α2c‐AR resulted in improved PM expression and a reduction in IC retention in HEK 293 and Rat1 fibroblast cell lines. Conversely, transplantation of the α2c‐AR trafficking signal into the α2a‐AR resulted in restricted plasma membrane expression and IC retention. The presence of an evolutionary conserved trafficking signal within the α2c‐AR suggests a yet to be identified retention protein restricting its plasma membrane expression.