Grant-in-Aid for International Scientific Research.
|Section||Joint Research .|
|Research Institution||Hyogo University|
KITO Shozo Research Institute of Hyogo University, Professor, 附属研究所, 教授 (00010140)
BIGGIO G. University of Cagliari, Department of Experimental Biology, Professor, Department of Exp, 教授
BARNARD E.A Camoridge University Department of Pharm, 教授
OLSEN R W UCLA School of Medicine, 教授
野村 靖幸 北海道大学, 薬学部, 教授 (00034041)
TOHYAMA Masaya Osaka University, School of Medicine, Professor, 医学部, 教授 (40028593)
SHINGO Akiko Research Institute of Hyogo University, Assistant Professor, 附属研究所, 講師 (50309499)
OLSEN R.W UCLA School of Medicine, 教授
BARNARD E.A. Cambridge University, Department of Pharmacology, Professor, 教授
OLSEN R.W. UCLA School of Medicine, Department of Pharmacology, Professor, 教授
|Project Fiscal Year
1997 – 1998
Completed(Fiscal Year 1998)
|Budget Amount *help
¥6,300,000 (Direct Cost : ¥6,300,000)
Fiscal Year 1998 : ¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1997 : ¥3,300,000 (Direct Cost : ¥3,300,000)
|Keywords||estrogen / IGF-1 mRNA / c-fos mRNA / AP-1 DNA binding activities / CREB DNA binding activities / Ca ion / nifedipine / tamoxifen / エストロゲン / IGF-1mRNA / c-fosmRNA / AP-1結合活性 / CREB結合活性 / Caイオン / IGF・1〜RNA / 海馬 / 大脳皮質 / GAP43〜RNA / カイニン酸 / Ca拮抗薬|
In our foregoing studies, we found that estrogen increased the survival rate of cultured rat hippocampal neurons. Then, we confirmed that a general injection of 0.5mg/kg beta-estradiol induced IGF-1 mRNA expression in the rat cerebral cortex as well as hippocampus.
Motivated by these facts, we have been trying to pursuit the signal transduction passway through which estrogen induces IGF-1 mRNA expression, and have so far obtained the following results.
1. Estrogen caused a transient increase of intracellular Ca ion concentration in some population of cultured rat hippocampal neurons. This increase was inhibited by nifedipine.
2. A general injection of 0.5mg/kg beta-estradiol Induced c-fos mRNA expression reaching the maximum at 3OmIn after the injection in the rat cerebral cortex and hippocampus.
3. A subcutaneous injection of 0.5mg/kg beta-estradiol potentiated the AP-1 DNA binding activities in both hippocampus and cerebral cortex reaching the maximum at 120min.
4. A subcutaneous injectio
n of 0.5mg/kg beta-estradiol increased the CREB (cyclic AMP response element binding protein) DNA binding activities in both cerebral cortex and hippocampus. The increase started at 45mm after the injection and the binding was continuously incremental up to 120min in the hippocampus. In the cerebral cortex, the increase of the CREB DNA binding activities was transient.
5. When observed by RNase protection assay in the rat hippocarnpus, estrogen-induced IGF-1 mRNA expression was blocked by a previous injection of nifedipine, but not inhibited by tamoxifen, a nuclear estrogen receptor partial antagonist.
6. Recently, it is advocated that there are estrogen specific binding sites not only in the nucleus but also on the cell membrane in which they are conjugated with G protein in relation with cyclic AMP.in our experiments, it was shown that in the hlppocarnpus, estrogen caused an upregulation of estrogen receptor alpha which was inhibited by nicotine . These phenomena were due to the complicated crosstalk among the newly-discovered membranous estrogen binding site, classical nuclear estrogen receptor and nicotinic receptor.
Summarizing these results, it was concluded that estrogen-induced cyclic AMP-dependant intraneuronal Ca ion concentration caused increase of CREB DNA binding activity, induction of c-fos mRNA expression and then increase of AP-1 DNA binding activIties in succession, and finally brought about induction of IGF-1 mRNA expression. Less