It has been proposed that extracellular ATP (ATPo) may function as a cytotoxic molecule in Ca(2+)-independent cell-mediated lysis by activating plasma membrane P2 purinergic receptors. In the present study the involvement of the P2z purinergic receptor in ATPo as well as cell-mediated lysis was investigated by using the J774 mouse macrophage cell line, which expresses this receptor, and a panel of J774-derived mutant cell clones selected for the lack of P2z receptor activity. We confirmed that the P2z receptor in J774 is associated with ATPo-induced colloido-osmotic lysis but not with apoptosis. Furthermore, we observed that the lack or the inhibition of the P2z purinergic receptor does not affect lytic activity mediated by different types of cytotoxic cell populations. These results on the whole indicate that the P2z receptor is involved in cell membrane damage induced by ATPo but not in cell-mediated cytotoxicity.