Complementary roles of the DRY motif and C-terminus tail of GPCRS for G protein coupling and β-arrestin interaction

beta-arrestin mediates the desensitization of GPCRs and acts as an adaptor molecule to recruit the receptor complex to clathrin-rich regions. Class-A GPCRs subsequently dissociate from beta-arrestin but class-B GPCRs internalize with P-arrestin in the endocytic vesicles. Here the dopamine D-2 and D-3 receptors, which have similar structural features but different intracellular trafficking properties, were used in an attempt to better understand the structural requirements for the classification of GPCRs. The C-terminus tail of the vasopressin type-2 receptor was added to the ends of D2R and D3R to increase their affinity to beta-arrestin. A point mutation was introduced into the DRY motif to change their basal activation levels. Among a battery of constructs in which the C-terminus tail and/or DRY motif was altered, class-B behavior was observed with the constructs whose affinities for P-arrestin were increased complementarily and their signaling was either maintained or regained. In conclusion, the DRY motif and C-terminal tail of the GPCRs determine complementarily their intracellular trafficking behavior by regulating the affinity to beta-arrestin and G protein coupling. (C) 2007 Elsevier Inc. All rights reserved.