P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease.
Primary rat microglia stimulated with either ATP or 2'- and 3'-O-(4-benzoylbenzoyl)-ATP (BzATP) release copious amounts of superoxide (O(2)(-)*). ATP and BzATP stimulate O(2)(-)* production through purinergic receptors, primarily the P2X(7) receptor. O(2)(-)* is produced through the activation of the NADPH oxidase. Although both p42/44 MAPK and p38 MAPK were activated rapidly in cells stimulated with BzATP, only pharmacological inhibition of p38 MAPK attenuated O(2)(-)* production. Furthermore, an inhibitor of phosphatidylinositol 3-kinase attenuated O(2)(-)* production to a greater extent than an inhibitor of p38 MAPK. Both ATP and BzATP stimulated microglia-induced cortical cell death indicating this pathway may contribute to neurodegeneration. Consistent with this hypothesis, P2X(7) receptor was specifically up-regulated around beta-amyloid plaques in a mouse model of Alzheimer's disease (Tg2576).
Parvathenani
Lav K
LK
Neuroscience Drug Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb Co., Wallingford, Connecticut 06492, USA. bparvathenani@curagen.com
Tertyshnikova
Svetlana
S
Greco
Corinne R
CR
Roberts
Susan B
SB
Robertson
Barbara
B
Posmantur
Rand
R
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000502:physiology; D002540:Cerebral Cortex / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D013481:Superoxides / Q000378:metabolism*; D015854:Up-Regulation
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; C546470:P2rx7 protein, rat; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013481:Superoxides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D019255:NADPH Oxidases; D002118:Calcium