Evidence implicates a number of neuroactive substances and their receptors in mediating complex cell-to-cell communications in the taste bud. Recently, we found that ATP, a ubiquitous neurotransmitter/neuromodulator, mobilizes intracellular Ca2+ in taste cells by activating P2Y receptors. Here, P2Y receptor-cellular response coupling was characterized in detail using single cell ratio photometry and the inhibitory analysis. The sequence of underlying events was shown to include ATP-dependent activation of PLC, IP3 production, and IP3 receptor-mediated Ca2+ release followed by Ca2+ influx. Data obtained favor SOC channels rather than receptor-operated channels as a pathway for Ca2+ influx that accompanies Ca2+ release. Intracellular Ca2+ mobilized by ATP is apparently extruded by the plasma membrane Ca2+-ATPase, while a contribution of the Na+/Ca2+ exchange and other mechanisms of Ca2+ clearance is negligible. Cyclic AMP-dependent phosphorylation is likely to control a gain of the phosphoinositide cascade involved in ATP transduction. ATP-responsive taste cells are abundant in circumvallate, foliate, and fungiform papillae. Taken together, our observations point to a putative role for ATP as a neurotransmitter operative in the taste bud.