Gustatory perception arises not only from intracellular transduction cascades within taste receptor cells but also from cell-to-cell communication among the cells of the taste bud. This study presents novel data demonstrating that the brain-gut peptide cholecystokinin (CCK) is expressed in subsets of taste receptor cells, and that it may play a signaling role unknown previously within the taste bud. Immunocytochemistry revealed positively stained subsets of cells within taste buds throughout the oral cavity. These cells typically displayed round nuclei with full processes, similar to those classified as light cells. Peptide expression was verified using nested PCR on template cDNA derived from mRNA extracted from isolated posterior taste buds. Multiple physiological actions of cholecystokinin on taste receptor cells were observed. An outward potassium current, recorded with the patch-clamp technique, was inhibited by exogenous application of sulfated cholecystokinin octapeptide in a reversible and concentration-dependent manner. Pharmacological analysis suggests that this inhibition is mediated by CCK-A receptors and involves PKC phosphorylation. An inwardly rectifying potassium current, typically invariant to stimulation, was also inhibited by cholecystokinin. Additionally, exogenous cholecystokinin was effective in elevating intracellular calcium as measured by ratiometric techniques with the calcium-sensitive dye fura-2. Pharmacology similarly demonstrated that these calcium elevations were mediated by CCK-A receptors and were dependent on intracellular calcium stores. Collectively, these observations suggest a newly discovered role for peptide neuromodulation in the peripheral processing of taste information.