Calcium-dependent prevention of neuronal apoptosis by lithium ion: essential role of phosphoinositide 3-kinase and phospholipase Cgamma.
We examined the possibility that the neuroprotective effects of Li+ would depend upon the patterns of neuronal death, apoptosis versus necrosis, and whether Ca2+ as well as phosphoinositide 3-kinase (PI3-K) would mediate the neuroprotective effect of Li+. Cortical neurons treated with Li+ showed marked increase in [Ca2+]i within 2 min. Addition of BAPTA-acetoxymethyl ester, a selective Ca2+ chelator, abrogated the antiapoptotic effect of Li+. PI3-K was activated rapidly within 1 min after exposure to Li+, which mediated Ca2+-dependent neuroprotective effects of Li+. Activated PI3-K seemed to increase [Ca2+]i via the phospholipase Cgamma (PLCgamma) pathway. Antiapoptosis action of Li+ was prevented in the presence of U-73122, a selective phospholipase C inhibitor, and was not observed in PLCgamma1-null fibroblasts. In contrast to antiapoptosis action, administration of Li+ did not prevent neuronal cell necrosis by excitotoxicity or free radicals. Li+ selectively prevents apoptosis by increasing [Ca2+]i through activation of PI3-K and PLCgamma pathways.
Kang
Hyo Jung
HJ
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea, 442-749.
Noh
Jai Sung
JS
Bae
Yun Soo
YS
Gwag
Byoung Joo
BJ
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051966:Phospholipase C gamma; D010738:Type C Phospholipases / Q000502:physiology*
D008094:Lithium; D019869:Phosphatidylinositol 3-Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium