P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway.

Mandi Gandelman (1, 2) , Mark Levy (2) , Patricia Cassina (3) , Luis Barbeito (1, 4) , Joseph S Beckman (3)

1 Institut Pasteur de Montevideo
2 Linus Pauling Institute
3 Departamento de Histologia, Facultad de Medicina
4 IIBCE - Instituto de Investigaciones Biológicas Clemente Estable [Montevideo]

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.

Mots clés: nitric oxide; motorneurondisease; amyotrophic lateral sclerosis; purinergic; CD95; adenosine; nitric oxide.

Domaines: Sciences du Vivant [q-bio]

Mandi Gandelman, Mark Levy, Patricia Cassina, Luis Barbeito, Joseph S Beckman. P2X7 receptor-induced death of motor neurons by a peroxynitrite/FAS-dependent pathway.. Journal of Neurochemistry, 2013, 126 (3), pp.382-8. ⟨10.1111/jnc.12286⟩. ⟨pasteur-00847581⟩