RRC ID 44105
著者 Ishima T, Iyo M, Hashimoto K.
タイトル Neurite outgrowth mediated by the heat shock protein Hsp90α: a novel target for the antipsychotic drug aripiprazole.
ジャーナル Transl Psychiatry
Abstract Aripiprazole is an atypical antipsychotic drug approved for the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and autism. The drug shows partial agonistic activity at dopamine D(2) receptors and 5-hydroxytryptamine (5-HT) 5-HT(1A) receptors, and antagonistic activity at 5-HT(2A) receptors. However, the precise mechanistic pathways remain unclear. In this study, we examined the effects of aripiprazole on neurite outgrowth. Aripiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. The 5-HT(1A) receptor antagonist WAY-100635, but not the dopamine D(2) receptor antagonist sulpiride, blocked the effects of aripiprazole, although, only partially. Specific inhibitors of inositol 1,4,5-triphosphate (IP(3)) receptors and BAPTA-AM, a chelator of intracellular Ca(2+), blocked the effects of aripiprazole. Moreover, specific inhibitors of several common signaling pathways phospholipase C-γ (PLC-γ), phosphatidylinositol-3 kinase (PI3K), mammalian target of rapamycin, p38 MAPK, c-Jun N-terminal kinase, Akt, Ras, Raf, ERK, MAPK) also blocked the effects of aripiprazole. Using proteomic analysis, we found that aripiprazole significantly increased levels of the heat shock protein Hsp90α in cultured cells. The effects of aripiprazole on NGF-induced neurite outgrowth were significantly attenuated by treatment with Hsp90α RNA interference, but not by the negative control of Hsp90α. These findings suggest that both 5-HT(1A) receptor activation and Ca(2+) signaling via IP(3) receptors, as well as their downstream cellular signaling pathways play a role in the promotion of aripiprazole-induced neurite outgrowth. Furthermore, aripiprazole-induced increases in Hsp90α protein expression may form part of the therapeutic mechanism for this drug.
巻・号 2(10)
ページ e170
公開日 2012-10-16
DOI 10.1038/tp.2012.97
PII tp201297
PMID 23047241
PMC PMC3565827
MeSH Analysis of Variance Animals Antipsychotic Agents / pharmacology* Aripiprazole Heat-Shock Proteins / genetics Heat-Shock Proteins / metabolism* Immunohistochemistry Inositol 1,4,5-Trisphosphate Receptors / antagonists & inhibitors* Nerve Growth Factor Neurites / drug effects* Neurites / metabolism PC12 Cells Piperazines / pharmacology* Proteomics Quinolones / pharmacology* RNA Interference Rats Receptor, Serotonin, 5-HT1A / metabolism* Receptors, Dopamine D2 / metabolism Signal Transduction / drug effects*
IF 5.28
引用数 28
WOS 分野 PSYCHIATRY
リソース情報
ヒト・動物細胞 PC-12(RCB0009)