Calcium-Dependent Prevention of Neuronal Apoptosis by Lithium Ion: Essential Role of Phosphoinositide 3-Kinase and Phospholipase Cγ

• DOI: 10.1124/mol.64.2.228
• Publication Date: 2003-07-17T21:32:25Z
• Authors: Hyo Jung Kang; Jai Sung Noh; Yun Soo Bae; Byoung Joo Gwag
• Keywords: Neurons; Mice, Inbred ICR; 0303 health sciences; Phospholipase C gamma; Apoptosis; Lithium; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Type C Phospholipases; Animals; Humans; Calcium; Drug Interactions

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.