Structure, function and regulation of the Na^+/H^+ exchanger

Na^/H^交换器的结构、功能和调控

• 批准号: 11680650
• 负责人: WAKABAYASHI Shigeo
• 金额: $ 2.37万
• 依托单位: National Cardiovascular Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680650/
• 关键词: Na^+; H^+ exchanger; membrane topology; mutagevesis; Volume regulation; Calcineurin-homologous protein; lithium ion; 細胞内pH; 細胞容積; カルシニューリン類似タンパク質

Mammalian Na^+/H^+ exchanger (NHE) is a ubiquitous plasma membrane transporter that regulates intracellular pH and cell volume, and epithelial absorption of Na^+ and bicarbonate in kidney and intestine. During 2 years, we studied about structure-function and regulatory mechanism of NHE, and obtained following results.1. We discovered that one of exchanger-binding proteins, calcineurin-homologous protein (CHP) is an essential cofactor for physiological activity of multiple exchanger isoforms (JBC, 2001, in press).2. Based on cysteine accessibility analysis, we presented a novel topology model of NHE1 (JBC, 2000).3. We identified critical amino acid residues important for plasma membrane expression of NHE1 and found that second mutations at several positions rescued surface expression of NHE1 (FEBS letters, 2000).4. We found that Li^+ ion is an activator of NHE isoforms NHE1 and NHE2, and tyrosine kinase may be involved in this activation process (Pflugers Archiv. 2000).5. We found that the extracellular loop is responsible for different volume sensitivity of NHE1 and NHE2 (submitted).

哺乳动物Na^+/H^+交换器（NHE）是一种普遍存在的质膜转运蛋白，可调节细胞内pH值和细胞体积，以及肾和肠上皮对Na^+和碳酸氢盐的吸收。在2年的时间里，我们对NHE的结构功能和调控机制进行了研究，得到了以下结果：我们发现交换器结合蛋白之一，钙调神经蛋白同源蛋白（CHP）是多种交换器异构体生理活性的重要辅助因子（JBC, 2001, in press）。基于半胱氨酸可及性分析，我们提出了一种新的NHE1拓扑模型（JBC, 2000）。我们确定了对NHE1质膜表达重要的关键氨基酸残基，并发现在几个位置的二次突变挽救了NHE1的表面表达（FEBS letters, 2000）。我们发现Li^+离子是NHE异构体NHE1和NHE2的激活剂，酪氨酸激酶可能参与了这一激活过程（Pflugers archiiv . 2000）。我们发现细胞外环对NHE1和NHE2的不同体积敏感性负责（提交）。

项目成果

Wakabayashi.S. et al.: "A Novel topology model of the human Na^+/H^+ exchanger NHE1."J.Biol.Chem.. 275. 7942-7949 (2000)

若林.S.

Kobayashi et al.: "Lithium activates mamalian Na^+/H^+ exchangers."PHugers Archiv. 439. 455-462 (2000)

Kobayashi 等人：“锂激活哺乳动物 Na^ /H^ 交换器。”PHugers Archive。

Kobayaslin et al.: "Lithium activates mammalian Na^+/H^+ exchangers."P Hugers Aochiv. 439. 455-462 (2000)

Kobayaslin 等人：“锂激活哺乳动物 Na^ /H^ 交换器。”P Hugers Aochiv。

Pang.T et al.: "Calcineurin homologous protein as an essential cofactor of the Na^+/H^+ exchangers"J.Biol.Chem.. in press. (2001)

Pang.T 等人：“钙调神经磷酸酶同源蛋白作为 Na + /H + 交换剂的重要辅助因子”J.Biol.Chem.. 正在出版。