Structure, function and regulation of the mammalian Na+/H+ antiporters

哺乳动物 Na /H 逆向转运蛋白的结构、功能和调节

• 批准号: 13142210
• 负责人: WAKABAYASHI Shigeo
• 金额: $ 47.68万
• 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 on Priority Areas
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13142210/
• 关键词: Na+; H+ antiporter; Intracellular pH; Crystal structure; Biochemistry; Biophysics; nanomachine; Biological Molecule; Protein; 蛋白質

We have studied about structure, function and regulation of the Na^-/II^+ oxchanger (NHE, SLC9 family), in terms of i) mechanism of ion transport and pH-sensing, structure-function of regulatory cofactor CHP and involvement of NHE and its related proteins in diseases. (1)Mechanism of ion transport and pH-sensing. We elucidated the existence of "Wregulatory sites" in NHE1-NHE3 by measuring the reverse mode of exchange (^<22>Na^+-efllux) and identified several critical residues in NHE1 to regulate such H+-sites. We also identified the critical region regulating volume-sensing, and recently found that dimerization may be essential for the physiological activity of NHE. (2)Structure-function of CHP. We found that CHP is an essential cofactor for the plasma membrane exchangers (NHE1-3) to support the physiological activity and the second isoform CHP2 may be involved in maintenance of high pHi in cancer cells. Recently, we solved the crystal structure of CHP2 complexed with the NHE1-fragment and discovered the molecular mechanism for tight association between CHP/NHE. (3)Involvement of NHE or its related proteins in diseases. We found that in hypertrophied cardiac muscles the Na^-/Ca^<2+> exchanger is inhibited by calcineurin which is a major signaling molecule which leads to cardiac hypertrophy.

本论文从离子转运和pH敏感机制、调控辅因子CHP的结构与功能以及NHE及其相关蛋白在疾病中的作用等方面对NHE的结构、功能和调控进行了研究。（1）离子迁移和pH敏感机理。我们通过测量交换的反向模式（^ Na^+-流出）阐明了NHE 1-NHE 3中“W调节位点”的存在<22>，并确定了NHE 1中调节这些H+-位点的几个关键残基。我们还确定了调节体积感知的关键区域，最近发现二聚化可能是NHE生理活性所必需的。（2）CHP的结构与功能。我们发现CHP是质膜交换器（NHE 1 -3）支持生理活性的必要辅因子，并且第二亚型CHP 2可能参与维持癌细胞中的高pHi。最近，我们解决了与NHE 1片段复合的CHP 2的晶体结构，并发现了CHP/NHE之间紧密缔合的分子机制。（3）NHE或其相关蛋白参与疾病。我们发现，在肥大的心肌中，Na^-/Ca^&lt;2+&gt;交换被钙调神经磷酸酶抑制，钙调神经磷酸酶是导致心肌肥大的主要信号分子。

项目成果

Su, X., et al.: "Evidence for involvement of the putative first extracellular loop in differential volume-sensitivity of the Na^+/H^+ exchangers NHE1 and NHE2."Biochemistry. 42. 1086-1094 (2003)

Su, X., 等人：“推定的第一个细胞外环参与 Na^/H^ 交换器 NHE1 和 NHE2 的体积敏感性差异的证据。”生物化学。

Expression of Calcineurin B Homologous Protein 2 Protects Serum Deprivation-Induced Cell Death by Serum-Independent Activation of Na+/H+ exchanger 1.

钙调神经磷酸酶 B 同源蛋白 2 的表达通过 Na /H 交换器 1 的血清依赖性激活来保护血清剥夺诱导的细胞死亡。

• 发表时间: 2002
• 期刊: J. Biol. Chem. 277(46)
• 作者: Pang;T.;Wakabayashi;S.;Shigekawa;M.
• 通讯作者: M.

Mechanism of acid adaptation of a fish living in a pH 3.5 lake

• DOI: 10.1152/ajpregu.00267.2002
• 发表时间: 2003-05-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
• 影响因子: 2.8
• 作者: Hirata, T;Kaneko, T;Hirose, S
• 通讯作者: Hirose, S

Novel role of neuronal Ca2+ sensor-1 as a survival factor up-regulated in injured neurons

• DOI: 10.1083/jcb.200508156
• 发表时间: 2006-03-27
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Nakamura, TY;Jeromin, A;Nabekura, J
• 通讯作者: Nabekura, J

Role of calcineurin B homologous protein in pH regulation by the Na+/H+ exchanger 1: tightly bound Ca2+ ions as important structural elements.

• DOI: 10.1021/bi0360004
• 发表时间: 2004-03
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: T. Pang;T. Hisamitsu;H. Mori;M. Shigekawa;S. Wakabayashi