The ATP release channel Pannexin1 (Panx1) is self-regulated, i.e. the permeant 
ATP inhibits the channel from the extracellular space. The affinity of the ATP 
binding site is lower than that of the purinergic P2X7 receptor allowing a 
transient activation of Panx1 by ATP through P2X7R. Here we show that the 
inhibition of Panx1 by ATP is abrogated by increased extracellular potassium ion 
concentration ([K(+)]o) in a dose-dependent manner. Since increased [K(+)]o is 
also a stimulus for Panx1 channels, it can be expected that a combination of ATP 
and increased [K(+)]o would be deadly for cells. Indeed, astrocytes did not 
survive exposure to these combined stimuli. The death mechanism, although 
involving P2X7R, does not appear to strictly follow a pyroptotic pathway. 
Instead, caspase-3 was activated, a process inhibited by Panx1 inhibitors. These 
data suggest that Panx1 plays an early role in the cell death signaling pathway 
involving ATP and K(+) ions. Additionally, Panx1 may play a second role once 
cells are committed to apoptosis, since Panx1 is also a substrate of caspase-3.