Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death.
AMP-activated protein kinase (AMPK), a member of the metabolite-sensing protein kinase family, is activated by energy deficiency and is abundantly expressed in neurons. The environmental pollutant, tributyltin chloride (TBT), is a neurotoxin, and has been reported to decrease cellular ATP in some types of cells. Therefore, we investigated whether TBT activates AMPK, and whether its activation contributes to neuronal cell death, using primary cultures of cortical neurons. Cellular ATP levels were decreased 0.5 h after exposure to 500 nM TBT, and the reduction was time-dependent. It was confirmed that most neurons in our culture system express AMPK, and that TBT induced phosphorylation of AMPK. Compound C, an AMPK inhibitor, reduced the neurotoxicity of TBT, suggesting that AMPK is involved in TBT-induced cell death. Next, the downstream target of AMPK activation was investigated. Nitric oxide synthase, p38 phosphorylation and Akt dephosphorylation were not downstream of TBT-induced AMPK activation because these factors were not affected by compound C, but glutamate release was suggested to be controlled by AMPK. Our results suggest that activation of AMPK by TBT causes neuronal death through mediating glutamate release.
Nakatsu
Yusuke
Y
Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Kotake
Yaichiro
Y
Hino
Atsuko
A
Ohta
Shigeru
S
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D009097:Multienzyme Complexes / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D014220:Trialkyltin Compounds / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D009097:Multienzyme Complexes; D014220:Trialkyltin Compounds; D018698:Glutamic Acid; C011559:tributyltin; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases