Redox Regulation of Signal Transduction Mechanism in the Heart

心脏信号转导机制的氧化还原调节

• 批准号: 13470483
• 负责人: KUROSE Hitoshi
• 金额: $ 9.28万
• 依托单位: Kyushu University (2002)The University of Tokyo (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470483/
• 关键词: reactive oxygen species; oxidative stress; cysteine residue; G protein; signaling molecule; intracellular mediator; 酸素毒性; 細胞保護; セリン変異体

Reactive oxygen species (ROS) has been considered as an 'evil player' due to a strong reactivity. We have reported that trimeric G protein (G_i/G_0) is directly activated by one of ROS hydrogen peroxide (H_2O_2) in rat neonatal myocytes. Upon activation of G_i/G_0 by H_2O_2, Gβγis released from trimeric G_i/G_0 and the released Gβγ activates ERK to protect the cells against oxidative damage. We have now identified the amino acids that are modified by H_2O_2, and have found that the H_2O_2-mediated modification of cysteine residues located at 287 and 326 is necessary for activation of G_i. These results indicate that ROS can work as an intracellular mediator in the heart, and suggest that ROS generated by receptor stimulation can activate G_i and G_0. Other than the treatment of cells with H_2O_2, ROS was generated by receptor stimulation. Although angiotensin II stimulation generated ROS and induced MAP kinase activation, angiotensin II stimulation could not activate G_i and G_0. Therefore, we concluded that the amount of ROS is an important factor for activation of G protein. We have also found that the expression of peroxiredoxin II (PrxII) eliminates ROS from cells, and PrxII abolishes c-Jun NH_2-terminal kinase (JNK) activation without affecting ERK and p38 MAPK activation. It is concluded that angiotensin II activates specific signaling pathway leading to JNK activation. It also suggests that ROS can work as an intracellular mediator.

活性氧（ROS）由于具有很强的反应性，一直被认为是“邪恶的玩家”。我们报道了三聚体G蛋白（G_i/G_0）被过氧化氢（H_2O_2）中的一种ROS直接激活。H_2O_2激活G_i/G_0后，三聚体G_i/G_0释放Gβγ，释放的Gβγ激活ERK，保护细胞免受氧化损伤。我们现在已经确定了被H_2O_2修饰的氨基酸，并发现H_2O_2介导的位于287和326的半胱氨酸残基的修饰是激活G_i所必需的。这些结果表明ROS可以作为心脏细胞内的介质，并且表明受体刺激产生的ROS可以激活G_i和G_0。与H_2O_2处理细胞不同，ROS是通过受体刺激产生的。虽然血管紧张素II刺激产生ROS并诱导MAP激酶激活，但血管紧张素II刺激不能激活G_i和G_0。因此，我们认为ROS的数量是G蛋白活化的重要因素。我们还发现过氧化物还蛋白II （PrxII）的表达消除了细胞中的ROS， PrxII消除了c-Jun nh_2末端激酶（JNK）的激活，而不影响ERK和p38 MAPK的激活。由此可见，血管紧张素II激活了JNK激活的特定信号通路。这也表明ROS可以作为细胞内介质起作用。

项目成果

Hara, Y. et al.: "LTRPC2 Ca2+-permeable channel activated by changes in redox confers susceptibility to cell death"Mol. Cell. 9. 163-172 (2002)

Hara, Y. 等人：“氧化还原变化激活的 LTRPC2 Ca2 渗透通道赋予细胞死亡敏感性”Mol。

Endo A., Nagashima K., Kurose H., Mochizuki S., Matsuda M., and Mochizuki N.: "Sphingosine 1-phosphate induces membrane ruffling and increases motility of human umbilical vein endothelial cells via vascular endothelial growth factor receptor and CrkII."J.

Endo A.、Nagashima K.、Kurose H.、Mochizuki S.、Matsuda M. 和 Mochizuki N.：“1-磷酸鞘氨醇通过血管内皮生长因子受体和 CrkII 诱导细胞膜褶皱并增加人脐静脉内皮细胞的运动性

Shiina, T.: "Clathrin box in G protein-coupled receptor kinase 2"J.Biol.Chem.. 276. 33019-33026 (2001)

Shiina, T.：“G 蛋白偶联受体激酶 2 中的网格蛋白盒”J.Biol.Chem.. 276. 33019-33026 (2001)

Nishida, M., Takagahara, S., Maruyama, Y., Sugimoto, Y., Nagao, T. and Kurose, H.: "Gβγ counteracts Gα_q signaling upon β_1-adrenergic receptor stimulation"Biochem. Biophys. Res. Commun.. 291. 995-1000 (2002)

Nishida, M.、Takagahara, S.、Maruyama, Y.、Sugimoto, Y.、Nagao, T. 和 Kurose, H.：“Gβγ 对抗 β_1-肾上腺素受体刺激时的 Gα_q 信号传导”Biochem。 .291.995-1000（2002）

Isogaya. M., Nagao, T., and Kurose, H.: "Enhanced cAMP response of the naturally occurring mutant of human β_3-adrenoceptor"Jpn. J. Pharamcol.. 88. 314-318 (2002)

Isogaya. M.、Nagao, T. 和 Kurose, H.：“人 β_3-肾上腺素受体天然突变体的增强 cAMP 反应”J. Pharamcol.. 88. 314-318 (2002)