Taste receptors are thought to couple to the G protein Gα-gustducin to initiate signal transduction cascades leading to taste perception. To further characterize the G protein-coupling selectivity of these receptors, we expressed them in HEK293 cells and monitored the modulation of different signaling pathways upon stimulation. We found that the bitter compound cycloheximide induces phosphorylation of extracellular signal-regulated kinases1 and 2 (ERK 1/2) and inhibits cAMP accumulation in HEK293 cells expressing the mouse bitter T2R5 receptor. These effects are totally abolished upon treatment with pertussis toxin. On the other hand, sweeteners and monosodium glutamate induce phosphorylation of ERK1/2 and inhibit cAMP accumulation in HEK293 cells expressing the human sweet T1R2/T1R3 receptor and the human umami T1R1/T1R3 receptor, respectively. The effects of these taste modalities are also prevented by treatment with pertussis toxin. Collectively, our results show that taste receptors can functionally couple to Gαi/o proteins to transmit intracellular signals. [Copyright &y& Elsevier]