钩藤甲素对电压依赖性L型钙通道亚单位α-1C的抑制作用:抑制电位和分子刺激。

PubMed ID
G H
发表日期 2020年Sep月

原始出处 国际生物大分子杂志
International journal of biological macromolecules
作者 Yun  Wei-Jing  Zhang  Xin-Yue  Liu  Tian-Tian  Liang  Jia-Hao  Sun  Cheng-Peng  Yan  Jian-Kun  Huo  Xiao-Kui  Tian  Xiang-Ge  Zhang  Bao-Jing  Huang  Hui-Lian  Ma  Xiao-Chi 

文献标题 钩藤甲素对电压依赖性L型钙通道亚单位α-1C的抑制作用:抑制电位和分子刺激。
The inhibition effect of uncarialin A on voltage-dependent L-type calcium channel subunit alpha-1C: Inhibition potential and molecular stimulation.
The inhibition effect of uncarialin A on voltage-dependent L-type calcium channel subunit alpha-1C: Inhibition potential and molecular stimulation.

文献摘要

近年来,高血压、心力衰竭等心血管疾病已成为威胁人类健康的最主要和全球性的原因。钩藤作为一种传统中药,长期以来被广泛应用于高血压病的治疗,但其有效成分及潜在作用机制尚不清楚。因此,从美国分离得到24种生物碱(1-24)。研究钩藤对苯肾上腺素(Phe)引起的大鼠肠系膜动脉收缩的舒张作用。其中,钩藤甲素(21)对苯丙氨酸引起的收缩(IC50=0.18μM)表现出最强的舒张作用,其舒张作用不依赖于内皮源性血管舒张因子和内皮细胞。所有实验包括用荧光显微镜、全细胞路径钳、分子对接和分子动力学测量血管平滑肌细胞(VSMC)中的Ca2+,证明钩藤甲素A(21)通过与氨基酸残基Met1186的氢键作用,能显著抑制L型钙通道亚单位α-1C(Cav1.2),抑制Ca2+内向电流。提示钩藤甲素A(21)可作为一种潜在的L型Cav1.2受体阻滞剂用于心血管疾病的有效治疗。


Cardiovascular diseases, such as hypertension and cardiac failure, have become the most major and global cause for threatening human health in recent years. Uncaria rhynchophylla as a traditional Chinese medicine is widely used to treat hypertension for a long history, whereas its medicinal effective components and potential action mechanism are uncertain. Therefore, twenty-four alkaloids (1-24) isolated from U. rhynchophylla were assayed for their relaxant effects against phenylephrine (Phe)-induced contraction of rat mesenteric arteries. Among them, we surprisingly found that uncarialin A (21) exhibited most potent relaxation effect against Phe-induced contraction (IC50 = 0.18 μM) in the manner of independent on endothelium-derived vasorelaxing factors and endothelium. All the experiments including measurement of Ca2+ in vascular smooth muscle cells (VSMCs) by fluorescence microscopy, whole-cell path clamp, molecular docking, and molecular dynamics, demonstrated that uncarialin A (21) could significantly inhibit L-type calcium channel subunit alpha-1C (Cav1.2) via the hydrogen bond interaction with amino acid residue Met1186, allowing the inhibition of Ca2+ inward current. Our results suggested that uncarialin A (21) could be served as a potential L-type Cav1.2 blocker in the effective treatment of cardiovascular diseases.

Cardiovascular diseases, such as hypertension and cardiac failure, have become the most major and global cause for threatening human health in recent years. Uncaria rhynchophylla as a traditional Chinese medicine is widely used to treat hypertension for a long history, whereas its medicinal effective components and potential action mechanism are uncertain. Therefore, twenty-four alkaloids (1-24) isolated from U. rhynchophylla were assayed for their relaxant effects against phenylephrine (Phe)-induced contraction of rat mesenteric arteries. Among them, we surprisingly found that uncarialin A (21) exhibited most potent relaxation effect against Phe-induced contraction (IC50 = 0.18 μM) in the manner of independent on endothelium-derived vasorelaxing factors and endothelium. All the experiments including measurement of Ca2+ in vascular smooth muscle cells (VSMCs) by fluorescence microscopy, whole-cell path clamp, molecular docking, and molecular dynamics, demonstrated that uncarialin A (21) could significantly inhibit L-type calcium channel subunit alpha-1C (Cav1.2) via the hydrogen bond interaction with amino acid residue Met1186, allowing the inhibition of Ca2+ inward current. Our results suggested that uncarialin A (21) could be served as a potential L-type Cav1.2 blocker in the effective treatment of cardiovascular diseases.


获取全文 10.1016/j.ijbiomac.2020.05.100