The purinergic receptor P2X₇ is part of a complex signaling mechanism participating in a variety of physiological and pathological processes. Depending on the activation scheme, P2X₇ receptors in vivo are non-selective cation channels or form large pores that can mediate apoptotic cell death. Expression of P2X₇R in Xenopus oocytes results exclusively in formation of a non-selective cation channel. However, here we show that co-expression of P2X₇R with pannexin1 in oocytes leads to the complex response seen in many mammalian cells, including cell death with prolonged ATP application. While the cation channel activity is resistant to carbenoxolone treatment, this gap junction and hemichannel blocking drug suppressed the currents induced by ATP in pannexin1/P2X₇R co-expressing cells. Thus, pannexin1 appears to be the molecular substrate for the permeabilization pore (or death receptor channel) recruited into the P2X₇R signaling complex.