Extracellular ATP mediates necrotic cell swelling in SN4741 dopaminergic neurons through P2X7 receptors.
Extracellular ATP has recently been identified as an important regulator of cell death in response to pathological insults. When SN4741 cells, which are dopaminergic neurons derived from the substantia nigra of transgenic mouse embryos, are exposed to ATP, cell death occurs. This cell death is associated with prominent cell swelling, loss of ER integrity, the formation of many large cytoplasmic vacuoles, and subsequent cytolysis and DNA release. In addition, the cleavage of caspase-3, a hallmark of apoptosis, is induced by ATP treatment. However, caspase inhibitors do not overcome ATP-induced cell death, indicating that both necrosis and apoptosis are associated with ATP-induced cell death and suggesting that a necrotic event might override the apoptotic process. In this study we also found that P2X(7) receptors (P2X(7)Rs) are abundantly expressed in SN4741 cells, and both ATP-induced swelling and cell death are reversed by pretreatment with the P2X(7)Rs antagonist, KN62, or by knock-down of P2X(7)Rs with small interfering RNAs. Therefore, extracellular ATP release from injured tissues may act as an accelerating factor in necrotic SN4741 dopaminergic cell death via P2X(7)Rs.
Jun
Dong-Jae
DJ
Department of Life Science, Division of Molecular and Life Science, Pohang University of Science and Technology, Nam-Gu, Pohang, Republic of Korea.
Kim
Jaeyoon
J
Jung
Sang-Yong
SY
Song
Ran
R
Noh
Ji-Hyun
JH
Park
Yong-Soo
YS
Ryu
Sung-Ho
SH
Kim
Joung-Hun
JH
Kong
Young-Yun
YY
Chung
Jun-Mo
JM
Kim
Kyong-Tai
KT
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D013997:Time Factors
C546469:P2rx7 protein, mouse; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D053148:Caspase 3; D004298:Dopamine