Regulation of extracellular matrix homeostasis via amino acid-operated cation channels

通过氨基酸操作的阳离子通道调节细胞外基质稳态

• 批准号: 23659042
• 负责人: NISHIDA Motohiro
• 金额: $ 2.41万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659042/
• 关键词: シグナル伝達; イオンチャネル; アミノ酸; 細胞外マトリクス; カルシウム; 薬学; 心血管; 細胞外マトリックス

Amino acids in vivo work not only as components of proteins, but also specificligands activating intracellular nutrition signalings. Although collapse of amino acid balance in vivo has been implicated in the development of several diseases, molecular target(s) connecting amino acid imbalance directly to diseases have not been identified. We identified proline-activated cation channel (PRAC), which is directly activated by extracellular matrix-composing amino acids, such as proline, hydroxyproline, alanine, and glycine. We demonstrated that diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6) participated as major components of PRAC in primary-cultured cardiomyocytes and cardiac fibroblasts. Deletion of TRPC3 or TRPC6 abolished amino acid-induced cation influx and subsequent increase in intracellular Ca2+concentration. We also found that autophagy was significantly induced in TRPC3- and TRPC6-deficient mouse hearts, and in cardiomyocytes treated with TRPC3/6 inhibitor. These findings strongly suggest that PRAC plays a critical role in protein recycling in the heart. On the other hand, overexpression of TRPC3 and TRPC6 conferred susceptibility to amino acid -induced Ca2+signaling in PRAC-nonexpressing cells. These results strongly suggest that TRPC3/6 heteromultimer channels function as PRAC.

氨基酸在体内不仅是蛋白质的组成成分，而且是激活细胞内营养信号的特定配体。虽然体内氨基酸平衡的破坏与多种疾病的发生有关，但氨基酸失衡与疾病直接相关的分子靶点尚未确定。我们确定了脯氨酸激活的阳离子通道（PRAC），它被细胞外基质组成的氨基酸，如脯氨酸、羟脯氨酸、丙氨酸和甘氨酸直接激活。我们证明了二酰基甘油激活的瞬时受体电位规范（TRPC）通道（TRPC3和TRPC6）在原代培养的心肌细胞和心脏成纤维细胞中作为PRAC的主要成分参与。删除TRPC3或TRPC6可消除氨基酸诱导的阳离子内流和随后的细胞内Ca2+浓度升高。我们还发现，TRPC3-和trpc6缺陷小鼠心脏以及TRPC3/6抑制剂处理的心肌细胞显著诱导自噬。这些发现有力地表明，PRAC在心脏蛋白质循环中起着关键作用。另一方面，TRPC3和TRPC6的过表达赋予了prac非表达细胞对氨基酸诱导的Ca2+信号的易感性。这些结果强烈提示TRPC3/6异质多分子通道具有PRAC的功能。

项目成果

Dual signaling pathways of arterial constriction by extracellular urine 5'-triphosphate in the rat

大鼠细胞外尿5-三磷酸收缩动脉的双重信号通路

• 发表时间: 2011
• 期刊: J. Pharmacol. Sci
• 作者: Sugihara M;Morita H;Matsuda M;Umebayashi H;Kajioka S;Ito S;Nishida M;Inoue R;Futatsuki T;Yamazaki J;Mori Y;Inoue R;Ito Y;Abe K and Hirata M
• 通讯作者: Abe K and Hirata M

硫化水素が心臓の老化を防ぐ仕組みを解明 〜心不全治療薬の開発に期待〜

阐明硫化氢防止心脏老化的机制 - 对心力衰竭治疗药物开发的期待 -

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实验室主页

硫化水素による心不全抑制の分子機構と創薬への応用

硫化氢抑制心力衰竭的分子机制及其在药物研发中的应用

• 发表时间: 2013
• 作者: Nishida M;Ishikawa T;Saiki S;Sunggip C;Aritomi S;Harada E;Kuwahara K;Hirano K;Mori Y;Kim-Mitsuyama S;Nishida M;西田基宏
• 通讯作者: 西田基宏

心臓の線維化におけるジアシルグリセロール活性化型TRPCチャネルの役割

二酰甘油激活的 TRPC 通道在心脏纤维化中的作用

• 发表时间: 2012
• 作者: Nishida M;Ishikawa T;Saiki S;Sunggip C;Aritomi S;Harada E;Kuwahara K;Hirano K;Mori Y;Kim-Mitsuyama S;Nishida M;西田基宏;西田基宏;Nishida M;西田基宏;西田基博;西田基宏，北島直幸，仲矢道雄，黒瀬等
• 通讯作者: 西田基宏，北島直幸，仲矢道雄，黒瀬等