The a-toxin from S.aureus is one of the most-studied toxins. Still, the basic mechanism of membrane-protein interactions is poorly understood. The toxin is able to lyse pure lipid membranes if they contain either sphingomyelin or phosphatidylcholine. Concentrations necessary to lyse liposomes are 200 nM and above, depending on the composition. In particular, sphingomyelin in the liquid-disordered phase increase oligomerisation efficiency (Schwiering 2013). In contrast, certain cells are lysed at low or sub-nanomolar concentrations. In the last years experimental evidence is accumulating which points towards a role of cellular responses for lysis, involving for example the ATP-gated P2X-channels (Skals 2011). In this context we studied the effect of P2X-inhibitors on lysis of rabbit-erythrocytes, which represent the class of very susceptible cells. The inhibitory concentrations of antagonists like PPADS, MRS2159 and BBG are in a similar range as reported for other erythrocytes and other toxins. Furthermore, treatment with hexokinase, oxATP, ATP or changes in extracellular calcium concentration did not alter lysis. Interestingly, we could show that in case of a-toxin the inhibitors PPADS and MRS2159 clearly interfere also with the interaction of the toxin with pure-lipid membranes, as evidenced by efflux-measurements, gel-electrophoresis and fluorescence microscopy. This does not exclude, that the observed inhibition in case of erythrocytes at least partially involves P2X-receptor. Such an involvement is supported by first observations that erythrocytes kept for a few days somewhat increase sensitivity towards the toxin, but distinctly decrease in response to PPADS. The results support that the whole lytic process induced by a-toxin is modulated by P2X-receptors to a different extent than RTX-toxins. We hope to get a clearer picture using toxin mutants, where first studies are under way. This work was supported by the DFG (SFB 490) and local support from the University of Mainz/ University Medical Center.