Apoptotic insults impair Na+, K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress.
The Na+, K+-ATPase (Na+, K+-pump) plays critical roles in maintaining ion homeostasis. Blocking the Na+, K+-pump may lead to apoptosis. By contrast, whether an apoptotic insult may affect the Na+, K+-pump activity is largely undefined. In cultured cortical neurons, the Na+, K+-pump activity measured as a membrane current Ipump was time-dependently suppressed by apoptotic insults including serum deprivation, staurosporine, and C2-ceramide, concomitant with depletion of intracellular ATP and production of reactive oxygen species. Signifying a putative relationship among these events, Ipump was highly sensitive to changes in ATP and reactive oxygen species levels. Moreover, the apoptosis-associated Na+, K+-pump failure and serum deprivation-induced neuronal death were antagonized by pyruvate and succinate in ATP- and reactive-oxygen-species-dependent manners. We suggest that failure of the Na+, K+-pump as a result of a combination of energy deficiency and production of reactive oxygen species is a common event in the apoptotic cascade; preserving the pump activity provides a neuroprotective strategy in certain pathological conditions.
Wang
Xue Qing
XQ
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA.
Xiao
Ai Ying
AY
Sheline
Christian
C
Hyrc
Krzystztof
K
Yang
Aizhen
A
Goldberg
Mark P
MP
Choi
Dennis W
DW
Yu
Shan Ping
SP
D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D007425:Intracellular Membranes / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D011233:Precipitin Tests; D019289:Pyruvic Acid / Q000494:pharmacology; D017382:Reactive Oxygen Species; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D019802:Succinic Acid / Q000494:pharmacology; D013997:Time Factors
C064769:N-acetylsphingosine; D017382:Reactive Oxygen Species; D000244:Adenosine Diphosphate; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D019802:Succinic Acid; D000254:Sodium-Potassium-Exchanging ATPase; D019311:Staurosporine; D013110:Sphingosine