Regulation of the cell surface traffic of α2‐adrenergic receptors by small GTPases

Abstract

The molecular mechanisms responsible for the cell surface targeting of nascent G protein‐coupled receptors (GPCRS) remain poorly elucidated. Our previous studies have utilized α2B‐adrenergic receptor (AR) as a model to define the pathways that mediate forward transport of GPCRs by studying the function of small GTPases in the Rab and ARF/Sar1 subfamilies. In this study, we compared the small GTPases‐coordinated cell surface movement of three α2‐ARs and investigated the possible mechanisms. Transient expression of dominant‐negative mutants of Rab, ARF, and Sar1 clearly inhibited the cell surface transport of α2A‐AR and α2C‐AR. Although the cell surface expression of α2A‐AR was much more abundant than that of α2C‐AR, their responsiveness to the small GTPase mutants was similar. In contrast, the cell surface transport of α2B‐AR was inhibited by some, but not all the mutants. More interestingly, three α2‐ARs differentially interacted with some small GTPases and the interaction was identified to be mediated via the third intracellular loops and/or the C‐terminal tails of the receptors. These data have demonstrated that the cell surface traffic of three α2‐ARs is controlled by different mechanisms and their differential interactions with different small GTPases involved in distinct transport steps along the secretory pathway may play an important role.