Pharmacological differentiation of the P2X7 receptor and the maitotoxin-activated cationic channel.
The ATP-P2X(7) receptor subtype and a maitotoxin-activated ion channel were studied to determine factors which identify them as separate entities in the control of a cytotolytic pore. Activation of ATP-P2X(7) receptors with 2'-3'-O-(benzylbenzyl) ATP (BzATP) or maitotoxin ion channels resulted in influx of ethidium bromide and cell death. Maitotoxin (25-250 pM)-induced ethidium bromide uptake and cell death was sensitive to extracellular Ca(2+), the ionic composition of the buffer, reduced by the calmodulin inhibitor W7, (N-(s-aminohexyl)-5-chloro-1-naphthalenesulfonamide), (10-100 microM) but unaffected by the ATP-P2X(7) receptor antagonist oxidized ATP, (adenosine 5'-triphosphate periodate oxidized sodium salt) (oATP). BzATP (10-200 microM)-induced ethidium bromide uptake and cell death were inhibited by oATP, unaffected by W7, inhibited by high ionic concentrations but only slightly dependant on external Ca(2+). These results are consistent with the existence of a pharmacological mechanism for controlling cell death consisting of an ATP-P2X(7) receptor, a maitotoxin-activated ion channel and a cytolytic pore.
Lundy
Paul M
PM
Medical Therapy Group, Chemical Biological Defence Section, Defence R&D Canada-Suffield, Box 4000, Medicine Hat, Alberta, Canada. Paul.Lundy@drdc-rddc.gc.ca
Nelson
Peggy
P
Mi
Lei
L
Frew
Robert
R
Minaker
Sean
S
Vair
Cory
C
Sawyer
Thomas W
TW
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D002021:Buffers; D016466:CHO Cells; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002412:Cations / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004996:Ethidium / Q000378:metabolism; D007473:Ion Channels / Q000187:drug effects*; D008387:Marine Toxins / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D035964:Oxocins / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis*; D058486:Receptors, Purinergic P2X7; D013449:Sulfonamides / Q000494:pharmacology; D000095702:Polyether Toxins
D000255:Adenosine Triphosphate; D002021:Buffers; D002147:Calmodulin; D002412:Cations; D004791:Enzyme Inhibitors; D004996:Ethidium; D007473:Ion Channels; D008387:Marine Toxins; D035964:Oxocins; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013449:Sulfonamides; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; C017967:W 7; C020394:maitotoxin; D000095702:Polyether Toxins