Aims: The purinergic P2X7 receptor is expressed in different types of cells, and it has varied functions including regulation of cell survival. The receptor is also expressed in exocrine glands, where it forms cation permeable channels, but its role in epithelial transport and secretion is unclear. The aim of our study was to determine whether the P2X7 receptor affects fluid secretion in pancreas, salivary glands and tear glands. Methods: For this study we used wild-type mice and P2X7-/- mice that were anaesthetised and stimulated with pilocarpine (10 mg/kg, I.P.) and secretion was collected from respective glands. We also made cells preparations from pancreas, parotid and lacrimal glands and measured ATP release and intracellular Ca²⁺ activity using fura-2. Results: The data shows that pancreatic secretion was reduced by 30% and salivary secretion by 70% in P2X7-/- mice (n=13, 9). In contrast, tear secretion was increased by 30-40% in P2X7-/- mice (n=7). ATP release in all cell preparations could be elicited by carbachol and other agonists and there was no difference between wild type and receptor knockout animals (n=7-10). ATP (0.1 mM) elicited 50% lower fura-2 peak responses in pancreatic cells from P2X7-/- animals (n=14,16). On the other hand, carbachol (0.05 mM) increased fura-2 peak responses by 40% in parotid and lacrimal cells of P2X7-/- animals. Conclusion: These results demonstrate that cholinergic stimulation leads to release of ATP that can via P2X7 receptors up-regulate pancreatic and salivary secretion but down- regulate tear secretion. Our data also indicate that there is an interaction between purinergic and cholinergic receptors or down-stream signalling. We conclude that the P2X7 receptor is important in short-term regulation of exocrine gland secretion.