We have compared the desensitization of two receptors, the thrombin receptor which displays dual coupling to both pertussis toxin-sensitive (Gi) and -insensitive (Gq) proteins and the serotonin type 2 (5-HT2) receptor which selectively couples to Gq. In the case of the thrombin receptor, cleavage induces activation and irreversible receptor modification followed by rapid (T1/2 = 3 min) and extensive desensitization of the receptor's ability to modulate phospholipase C (Gq). 5-HT-induced desensitization of its receptor is markedly slower (T1/2 = 10 min) and by 60 min only 50% of the phospholipase C response is lost. This effect occurs with a parallel disappearance of 5-HT receptors from the cell surface. Whole cell phosphorylation studies showed that the thrombin receptor is rapidly phosphorylated upon activation. In contrast, the 5-HT2 receptor displays a low basal level of phosphorylation which is not increased upon agonist treatment. The cytoplasmic tail of the 5-HT2 receptor which contains several protein kinase consensus sequences was found not to be involved in receptor activation or desensitization. However, a chimeric receptor having the core of the 5-HT2 receptor and the cytoplasmic tail of the thrombin receptor was able to undergo 5-HT-induced desensitization and phosphorylation. These results indicate that (i) both 5-HT2 and thrombin receptors have unique shut-off mechanisms, and (ii) that sequences in the carboxyl terminus of the thrombin receptor are sufficient to trigger rapid uncoupling of the receptor from its G protein(s) and downstream effector(s).