2005 Fiscal Year Final Research Report Summary
Regulation of cell growth and brain function by polyamines
| Project/Area Number |
16390018
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Chiba University |
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Principal Investigator |
IGARASHI Kazuei Chiba University, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学研究院, 教授 (60089597)
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| Co-Investigator(Kenkyū-buntansha) |
KASHIWAGI Keiko Chiba University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究院, 助教授 (80169424)
NISHIMURA Kazuhiro Chiba University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学研究院, 講師 (60302569)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Polyamine / Modulon / Spermidine / Spermine / NMDA receptor / Anthraquinone spermidine / Acrolein / Stroke |
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| Research Abstract |
1. We have reported previously that the synthesis of specific proteins such as OppA, Cya and RpoS (σ^<38>), which are important for cell growth, is stimulated by polyamines at the level of translation in E.coli. We found that the synthesis of FecI and Fis was also stimulated by polyamines at the level of translation. The FecI and Fis enhance expression of mRNAs that are involved in iron uptake and energy metabolism, and of rRNA and some tRNAs. The Shine-Dalgarno (SD) sequence of their mRNAs was not located at the usual position. When the SD sequences were created at the normal position on these mRNAs, protein synthesis was no longer influenced by polyamines. Thus, the common characteristic of these mRNAs was to have a weak SD sequence. We propose that a group of genes whose expression is enhanced by polyamines at the level of translation is referred to as a "polyamine modulon".
2. The effects of various anthraquinone polyamines (AQP) were studied at NMDA receptors expressed in Xenopus l
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aevis oocytes. All AQP derivatives inhibited responses of NR1/NR2 receptors in oocytes voltage-clamped at -70mV, with IC_<50> values between 4 and 22μM. The block was strongly voltage-dependent. AQ spermidine (AQ34) inhibited responses of NR1/NR2 receptors but did not inhibit responses of AMPA receptors indicating that AQ34 is preferential NMDA antagonists. Results of experiments using mutant NR1 and NR2 subunits identified residues that influence block by AQ34. These residues are located in the outer vestibule at the selectivity filter/narrowest constriction of the channel and in the inner vestibule below the level of the selectivity filter.
3. The levels of acetylpolyamine oxidase (AcPAO), spermine oxidase (SMO), and acrolein were significantly increased in the plasma of stroke patients. The size of stroke was nearly parallel with the multiplied value of acrolein and total polyamine oxidase (AcPAO plus SMO). After the onset of stroke, an increase in AcPAO first occurred, followed by increased level of SMO and finally acrolein. In 1 case, an increase in AcPAO and SMO preceded focal damage as detected by MRI or CT. Furthermore, stroke was confirmed by MRI in a number of mildly symptomatic patients (11 cases) who had increased levels of total polyamine oxidase and acrolein. The results indicate that AcPAO, SMO, and acrolein are good markers of stroke. Less
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