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.

体内的氨基酸不仅作为蛋白质的成分，而且还可以激活细胞内营养信号。尽管体内氨基酸平衡的崩溃与多种疾病的发展有关，但尚未发现将氨基酸失衡与疾病连接到疾病的分子靶标。我们鉴定了脯氨酸激活的阳离子通道（PRAC），该通道直接被细胞外基质组合的氨基酸（例如脯氨酸，羟基丙烯，丙氨酸和甘氨酸）激活。我们证明了二酰基甘油激活的瞬态受体电位典型（TRPC）通道（TRPC3和TRPC6）作为PRAC的主要成分参与初级培养的心肌细胞和心脏成纤维细胞。 TRPC3或TRPC6的缺失消除了氨基酸诱导的阳离子涌入，随后细胞内Ca2+浓度增加。我们还发现，在TRPC3和TRPC6缺陷的小鼠心脏以及用TRPC3/6抑制剂治疗的心肌细胞中，自噬显着诱导。这些发现强烈表明，PRAC在心脏中的蛋白质回收中起关键作用。另一方面，TRPC3和TRPC6的过表达赋予了对氨基酸诱导的Prac -Nonexpressing细胞中Ca2+信号的敏感性。这些结果强烈表明TRPC3/6异杀剂通道充当PRAC。

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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〜

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心臓リモデリングにおけるTRPCチャネルの役割

TRPC通道在心脏重构中的作用

• 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;西田基宏
• 通讯作者: 西田基宏

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