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Modulation of α‐2C Adrenergic Receptor intracellular trafficking by arginine‐based motifs

The upregulation of α2C‐adrenergic receptor (α2C‐AR) plasma membrane levels by exposure to cold contributes to the enhanced vasoconstriction observed in Raynaud Phenomenon. To understand this particular intracellular trafficking, we used α2C‐AR transfected HEK293T. Exposure to 30°C significantly enhanced α2C‐AR plasma membrane levels (69 ± 10 %), as determined by [3H]‐RX821002 binding. Sequence analysis demonstrated that eleven putative arginine based motifs (RXR) are embedded in in the C‐terminus and in the third intracellular loop of α2C‐AR, which were shown in other proteins to determine endoplasmic reticulum retention. Deletion of these RXR motifs had no effect on the α2C‐AR plasma membrane levels at 37°C, but it accentuates the upregulation at 30°C. Using alanine‐mutagenesis we identified two specific arginine clusters, which are augmenting the receptor trafficking at 30°C. This conclusion is supported by the absence of these motifs in the opossum α2C‐AR which lacks the temperature‐sensitive traffic. Also, one specific arginine cluster is shifted to the left in rat and mice α2C‐AR, which displayed a reduced augmentation of the receptor levels at the plasma membrane after exposure to 30°C (37 ± 6 % and 32 ± 5 %). Our data indicate that strict spatial positioning of arginine‐based motifs embedded in α2C‐AR is essential in prevention of exaggerated vasoconstriction to cold. NIH GrantP20RR018766‐08