Despite a high Ca2+ -permeability of the P2Z receptor in human B lymphocytes, extracellular ATP4- has only a minor effect on global [Ca2+]i. The aim of this study was to reveal the mechanisms responsible for this discrepancy. We investigated the relationship between ATP4- -application, Cai 2+ -response, membrane current and membrane potential in two human B cell lines and in human tonsillar B cells. This was achieved by a combination of FACS- and voltage clamp measurements and the usage of appropriate voltage- and Ca2 -sensitive fluorescent dyes. ATP4 -induced changes in whole-cell current and [Ca2]i were blocked by extracellular as well as intracellular Na+. Under current clamp conditions, ATP4- -induced Na+ -entry diminished the Ca2+ entry via reduction of the driving force. A substantial increase in [Ca2+]iinduced by ATP4- was only observed in Na+ -free solutions. The pathway of signal transduction activated by ATP4via P2Z receptor of human B lymphocytes under physiological conditions seems not to operate by an increase in the global intracellular Ca2+ -concentration, but rather by the depolarization of the cell membrane as a result of the Na+-influx. Copyright 2001 Harcourt Publishers Ltd.