ATP‐gated P2X7 Receptor (X7R) channel is linked to cell death. Function of X7R is regulated by P2X4 Receptor (X4R) independent of X4R channel function and independent of formation of heterotrimeric channel. Mechanism by which this interaction takes place remains unsettled and the physiological consequences of such interaction remain partially characterized. We used Fluorescence Resonance Energy Transfer technique (FRET) and fluorescence labeled X4R and X7R expressed in HEK293 cells to analyze the interaction between these receptors. We found that the FRET signal increased after activation of X7R with 100 uM BzATP. Activation of X4R with 20 μM ATP (does not activates X7R) did not increase the FRET signal. Because the fluorescence label was fused to the carboxyl tail of X7, our result suggests X7R interacts with X4R via a conformational change of the carboxyl tail. This hypothesis was further supported by coimmunoprecipitation of X4R and the X7R carboxyl tail. To test if the X4R/X7R interaction was physiologically relevant we evaluated cell death after activation of X7R in murine macrophages. Resident peritoneal macrophages were isolated from both wild type and X4R knockout (X4RKO) mice. Macrophages were stimulated with ATP and the solution was supplemented with YOPRO. Sudden increase in the YOPRO fluorescence indicated collapse of the nucleus, a irreversible phenomenon that leads to cell death. Death rate was slower in macrophages isolated from WT mice than in macrophages isolated from X4RKO mice. The percentage of cell death was significant greater in WT mice than in macrophages from X4RKO mice. Our results suggest that coexpression of X4R with X7R potentiate X7R‐dependent cell death. In macrophages co‐expression of X4R with X7R may be important for immune regulation. ATP‐induced cell death of immune cells could play an important role in termination of the immune response.