The interaction of a constitutively active arrestin with the arrestininsensitive 5-HT(2A) receptor induces agonistindependent internalization

5-HT2A serotonin receptors are unusual among G-protein cou-pled receptors in that they can be internalized and desensi-tized, in some cell types, in an arrestin-independent manner. The molecular basis of the arrestin-insensitivity of 5-HT2A re-ceptors is unknown but is probably caused, in part, by the apparent lack of agonist-induced 5-HT2A receptor phosphory-lation. Because the arrestin-insensitivity of 5-HT2A receptors is cell-type selective, we used a “constitutively active ” arrestin mutant that can interact with agonist-activated but nonphos-phorylated receptors. We show here that this “constitutively active ” arrestin mutant (Arr2-R169E) can force 5-HT2A recep-tors to be regulated by arrestins. Cotransfection of 5-HT2A receptors with Arr2-R169E induced agonist-independent 5-HT2A receptor internalization, and a constitutive translocatio