In single human gastric mucous cells extracellular ATP, ATP-gamma-S, ADP and UTP at micromolar concentrations caused a biphasic increase in [Ca2+]i. Consistent with a P2u-receptor the rank-order of potency was ATP > or = UTP > ATP-gamma-S > ADP, and cross-desensitization of the Ca2+ responses occurred between ATP and UTP. The initial transient peak in [Ca2+]i was resistant to extracellular Ca2+ depletion which demonstrates mobilization of internal Ca2+. By contrast, the sustained plateau phase required influx of external Ca2+. Ca2+ influx occurs most likely through a capacitative Ca2+ entry mechanism, which was shown to exist in these cells by experiments performed with thapsigargin. Thus, extracellular ATP and UTP activate a common P2u-receptor most likely coupled to the Ca(2+)-phosphatidylinositol signalling cascade. Extracellular nucleotides from various sources might be an important factor in the regulation of human gastric mucous cells.