ATP and potassium ions: a deadly combination for astrocytes.
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.
Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33136.
David G
DG
Jackson
Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33136.
Junjie
J
Wang
Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33136.
Robert W
RW
Keane
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, 10461.
Eliana
E
Scemes
Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33136.
Gerhard
G
Dahl
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D017630:Connexins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D007477:Ions / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014981:Xenopus / Q000254:growth & development
D017630:Connexins; D007477:Ions; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D053148:Caspase 3; D011188:Potassium