| Item type |
学位論文 / Thesis or Dissertation(1) |
| 公開日 |
2010-02-22 |
| タイトル |
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|
タイトル |
Regulation of volume-sensitive chloride channels by cystic fibrosis transmembrane conductance regulator and epidermal growth factor receptor |
| タイトル |
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タイトル |
Regulation of volume-sensitive chloride channels by cystic fibrosis transmembrane conductance regulator and epidermal growth factor receptor |
|
言語 |
en |
| 言語 |
|
|
言語 |
eng |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_46ec |
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資源タイプ |
thesis |
| 著者名 |
ABDULLAEV, Iskandar Fatkhullaevich
|
| フリガナ |
アブデルブ, イシカンダル
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| 著者 |
ABDULLAEV, Iskandar Fatkhullaevich
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| 学位授与機関 |
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学位授与機関名 |
総合研究大学院大学 |
| 学位名 |
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学位名 |
博士（理学） |
| 学位記番号 |
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内容記述タイプ |
Other |
|
内容記述 |
総研大甲第620号 |
| 研究科 |
|
|
値 |
生命科学研究科 |
| 専攻 |
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|
値 |
20 生理科学専攻 |
| 学位授与年月日 |
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|
学位授与年月日 |
2002-03-22 |
| 学位授与年度 |
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値 |
2001 |
| 要旨 |
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内容記述タイプ |
Other |
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内容記述 |
Effectene-mediated transient expression of wild-type (WT) human cystic fibrosis transmembrane conductance regulator (CFTR) in HEK293T cells resulted in a 3- times decrease of the amplitude of steady-state volume-sensitive outwardly rectifying (VSOR) chloride current, Expression of the CFTR ΔF508 mutant, which cannot be translocated to the plasma membrane， failed to mimic the CFTR effect on the VSOR Cl- current, suggesting that plasma membrane expression of CFTR protein is necessary for its regulatory effect on the VSOR Cl- channel. Expression of the G1349D mutant of CFTR, which impairs ATP binding to the NBD2 domain of CFTR protein， failed to inhibit VSOR Cl- currents．D1370N and K1250M mutations in NBD2 domain, which impair ATP hydrolysis， were also ineffective in down-regulating VSOR C1-currents．In contrast, expression of G551D mutant， which impairs ATP binding to the NBDl domain， mimicked the effect of WT- CFTR．Thus， I conclude that plasma membrane expression of an ATP- hydrolysable conformation of the NBD2 domain of CFTR is essential for its down-regulatory action on the volume-sensitive chloride conductance in HEK293T/CFTR cells．<br /><br />In mouse mammary gland C127 cells， in contrast, VSOR Cl- currents were up- regulated by stable expression of CFTR mediated by bovine papillomavirus （BPV)， a carrier for CFTR gene transfection， by around 3-fold．Also， BPV- mediated expression with CFTR ΔF508 mutant produced a similar up-regulating effect on VSOR Cl- currents．BPV expression is known to constitutively activate receptors to platelet-derived growth factor (PDGF) and epidermal growth factor （EGF)．Application of a PDGF peptide or a specific inhibitor of PDGF tyrosine kinase， tyrphostin AGl296， had no effect on VSOR Cl-currents．In contrast， application of an EGF peptide enhanced VSOR Cl-currents in Cl27 cells, but not in Cl27 cells treated with BPV(Cl27/BPV cells)．A specific inhibitor of EGF- receptor tyrosine kinase， tyrphostin B46， profoundly suppressed VSOR Cl-currents in Cl27 and Cl27/BPV cells．Thus， I conclude that VSOR Cl-channels are enhanced by an EGF receptor tyrosine kinase signaling and that BPV-induced up-regulation overrides CFTR-induced down-regulation of VSOR Cl-channels in Cl27/CFTR cells．Since inhibitors of phospholipase Cγ(PLCγ)， phosphatidylinositol-3-kinase (PI3K) and MAP kinase kinase (MEK) failed to affect the VSOR Cl-channel activity， it might be possible that the VSOR Cl- channel is regulated by some signaling pathway, other than those involving PLCγ，PI3K and MEK, which is downstream to the EGF receptor tyrosine kinase． |
| 所蔵 |
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値 |
有 |
| フォーマット |
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内容記述タイプ |
Other |
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内容記述 |
application/pdf |
要旨・審査要旨 / Abstract, Screening Result (208.6 kB)
