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Mitochondrial dysfunction is involved in P2X7 receptor‐mediated neuronal cell death
Author(s) -
Nishida Kentaro,
Nakatani Tsunetoshi,
Ohishi Akihiro,
Okuda Hiroto,
Higashi Youichirou,
Matsuo Takaaki,
Fujimoto Sadaki,
Nagasawa Kazuki
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07868.x
Subject(s) - carbenoxolone , programmed cell death , microbiology and biotechnology , pannexin , biology , mitochondrial permeability transition pore , mitochondrion , purinergic receptor , apoptosis , receptor , p2 receptor , biochemistry , extracellular , connexin , intracellular , gap junction
J. Neurochem . (2012) 122 , 1118–1128. Abstract P2X7 receptor (P2X7R) is known to be a ‘death receptor’ in immune cells, but its functional expression in non‐immune cells such as neurons is controversial. Here, we examined the involvement of P2X7R activation and mitochondrial dysfunction in ATP‐induced neuronal death in cultured cortical neurons. In P2X7R‐ and pannexin‐1‐expressing neuron cultures, 5 or more mM ATP or 0.1 or more mM BzATP induced neuronal death including apoptosis, and cell death was prevented by oxATP, P2X7R‐selective antagonists. ATP‐treated neurons exhibited Ca 2+ entry and YO‐PRO‐1 uptake, the former being inhibited by oxATP and A438079, and the latter by oxATP and carbenoxolone, while P2X7R antagonism with oxATP, but not pannexin‐1 blocking with carbenoxolone, prevented the ATP‐induced neuronal death. The ATP treatment induced reactive oxygen species generation through activation of NADPH oxidase and activated poly(ADP‐ribose) polymerase, but both of them made no or negligible contribution to the neuronal death. Rhodamine123 efflux from neuronal mitochondria was increased by the ATP‐treatment and was inhibited by oxATP, and a mitochondrial permeability transition pore inhibitor, cyclosporine A, significantly decreased the ATP‐induced neuronal death. In ATP‐treated neurons, the cleavage of pro‐caspase‐3 was increased, and caspase inhibitors, Q‐VD‐OPh and Z‐DEVD‐FMK, inhibited the neuronal death. The cleavage of apoptosis‐inducing factor was increased, and calpain inhibitors, MDL28170 and PD151746, inhibited the neuronal death. These findings suggested that P2X7R was functionally expressed by cortical neuron cultures, and its activation‐triggered Ca 2+ entry and mitochondrial dysfunction played important roles in the ATP‐induced neuronal death.