title: P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway.
abstract: The P2X7 receptor/channel responds to extracellular ATP and is associated with neuronal death and neuroinflammation in spinal cord injury and amyotrophic lateral sclerosis. Whether activation of P2X7 directly causes motor neuron death is unknown. We found that cultured motor neurons isolated from embryonic rat spinal cord express P2X7 and underwent caspase-dependent apoptosis when exposed to exceptionally low concentrations of the P2X7 agonist 2'(3')-O-(4-Benzoylbenzoyl)-ATP. The P2X7 inhibitors BBG, oATP, and KN-62 prevented 2'(3')-O-(4-Benzoylbenzoyl)-ATP-induced motor neuron death. The endogenous P2X7 agonist ATP induced motor neuron death at low concentrations (1-100 μM). High concentrations of ATP (1 mM) paradoxically became protective due to degradation in the culture media to produce adenosine and activate adenosine receptors. P2X7-induced motor neuron death was dependent on neuronal nitric oxide synthase-mediated production of peroxynitrite, p38 activation, and autocrine FAS signaling. Taken together, our results indicate that motor neurons are highly sensitive to P2X7 activation, which triggers apoptosis by activation of the well-established peroxynitrite/FAS death pathway in motor neurons.
authors: Neurodegeneration Laboratory, Institut Pasteur, Montevideo, Uruguay.
authors: Mandi
authors: M
authors: Gandelman
authors: Mark
authors: M
authors: Levy
authors: Patricia
authors: P
authors: Cassina
authors: Luis
authors: L
authors: Barbeito
authors: Joseph S
authors: JS
authors: Beckman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D009046:Motor Neurons / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D058486:Receptors, Purinergic P2X7; D019014:fas Receptor; D030421:Peroxynitrous Acid
keywords: CD95; adenosine; amyotrophic lateral sclerosis; motor neuron disease; nitric oxide; purinergic
references: Neuroreport. 2008 Nov 19;19(17):1715-9
references: 18852683
references: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):6007-12
references: 16581901
references: Arch Biochem Biophys. 2004 Mar 1;423(1):213-7
references: 14871483
references: J Biol Chem. 2010 Oct 29;285(44):33885-97
references: 20663894
references: Prog Neurobiol. 2006 Apr;78(6):327-46
references: 16697102
references: J Biol Chem. 2011 Dec 23;286(51):44035-44044
references: 22033929
references: Prog Brain Res. 1998;118:269-80
references: 9932448
references: J Neurochem. 2003 Apr;85(1):142-50
references: 12641736
references: J Cell Physiol. 2013 Feb;228(2):485-93
references: 22806078
references: J Cell Biol. 1999 Nov 29;147(5):1049-62
references: 10579724
references: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12489-93
references: 19666625
references: Drug News Perspect. 2005 Mar;18(2):85-101
references: 15883618
references: Neurochem Int. 2005 Nov;47(6):442-8
references: 16029911
references: FEBS J. 2009 Jan;276(2):354-64
references: 19076216
references: Biochem Soc Trans. 2007 Nov;35(Pt 5):1168-70
references: 17956304
references: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17210-5
references: 17940030
references: BMC Neurol. 2006 Mar 02;6:12
references: 16512913
references: J Comp Neurol. 2008 Jan 1;506(1):75-92
references: 17990272
references: J Neuroinflammation. 2010 Jun 09;7:33
references: 20534165
references: J Neurosci. 2007 Aug 29;27(35):9525-33
references: 17728465
references: Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):E1102-11
references: 23487751
references: Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8067-72
references: 18523012
references: J Biol Regul Homeost Agents. 2010 Jan-Mar;24(1):73-86
references: 20385073
references: J Neurosci. 2007 Jul 18;27(29):7777-85
references: 17634371
references: Arch Biochem Biophys. 1999 Dec 15;372(2):285-94
references: 10600166
references: Br J Pharmacol. 2009 Aug;157(7):1203-14
references: 19558545
references: Nat Med. 2004 Aug;10(8):821-7
references: 15258577
references: Neuron. 2002 Sep 12;35(6):1067-83
references: 12354397
references: Nat Rev Drug Discov. 2008 Jul;7(7):575-90
references: 18591979
references: Science. 1999 Dec 24;286(5449):2498-500
references: 10617463
references: J Immunol. 2009 Oct 1;183(7):4648-56
references: 19734218
references: J Biol Chem. 2007 Dec 28;282(52):37350-8
references: 17962183
references: Nat Rev Drug Discov. 2006 Mar;5(3):247-64
references: 16518376
references: FASEB J. 2009 Jun;23(6):1893-906
references: 19171786
references: Neurosci Lett. 1993 Mar 5;151(1):94-6
references: 8469442
references: Neurodegener Dis. 2005;2(3-4):139-46
references: 16909019
references: Free Radic Biol Med. 2006 Dec 1;41(11):1632-44
references: 17145551