Thrombin downregulates muscle acetylcholine receptors via an IP3 signaling pathway by activating its G‐protein‐coupled protease‐activated receptor‐1
Thrombin downregulates muscle acetylcholine receptors via an IP3 signaling pathway by activating its G‐protein‐coupled protease‐activated receptor‐1
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凝血酶通过 IP3 信号通路激活其 G 蛋白偶联蛋白酶激活受体 1，下调肌肉乙酰胆碱受体
DOI：
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发表时间：
2003
影响因子：
5.6
通讯作者：
D. Hantaı̈
中科院分区：
文献类型：
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作者：
B. Faraut;J. Barbier;A. Ravel;M. Doyennette;M. Jandrot;M. Verdiére;L. Schaeffer;Jeanine Koenig;D. Hantaı̈
在骨骼肌分化过程中可能需要调节凝血酶活性，因为凝血酶组织抑制剂蛋白酶nexin-1在定位于神经肌肉突触之前出现在肌管阶段。在这里，我们已经使用了一个模型，大鼠胎儿肌管原代培养研究凝血酶对乙酰胆碱受体（AChR）的表达，这是增强在肌管阶段的影响。我们的研究结果表明，凝血酶降低表面AChR（AChRn）和AChR α亚基基因表达的数量。使用激动剂肽SFLLRN，我们确定AChRn减少是由G蛋白偶联凝血酶受体“蛋白酶激活受体-1”（PAR-1）介导的。此外，特异性凝血酶抑制剂水蛭素通过抑制培养物中固有存在的凝血酶来增加AChRn。我们进一步证明，凝血酶激活PAR-1可诱导细胞内钙离子运动，而这种运动可被2-APB阻断，2-APB是肌醇1，4，5-三磷酸（IP 3）诱导的钙离子释放的抑制剂。这些钙信号在细胞核中比在细胞质中更强，并且与我们在细胞质中以横纹模式发现的IP 3受体的细胞内分布一致，并且在核膜区中处于高水平。最后，我们表明，这些IP 3诱导的钙信号的阻断2-APB阻止凝血酶诱导的AChRn减少。因此，我们的研究结果表明，凝血酶通过激活PAR-1下调AChR表达，这种作用是通过IP 3信号通路介导的。© 2003 Wiley利斯公司
Regulation of thrombin activity may be required during skeletal muscle differentiation since the thrombin tissue inhibitor protease nexin‐1 appears at the myotube stage before being localized at the neuromuscular synapse. Here, we have used a model of rat fetal myotube primary cultures to study the effect of thrombin on acetylcholine receptor (AChR) expression, which is enhanced at the myotube stage. Our results show that thrombin decreases both the number of surface AChRs (AChRn) and AChR α‐subunit gene expression. Using the agonist peptide SFLLRN, we establish that the AChRn decrease is mediated by the G protein‐coupled thrombin receptor “protease‐activated receptor‐1” (PAR‐1). Moreover, the specific thrombin inhibitor hirudin increases AChRn by inhibiting the thrombin intrinsically present in the cultures. We further demonstrate that the activation of PAR‐1 by thrombin induces intracellular calcium movements that are blocked by 2‐APB, an inhibitor of inositol 1,4,5‐triphosphate (IP3)‐induced calcium release. These calcium signals are more intense in nuclei than in the cytoplasm and are consistent with the intracellular distribution of IP3 receptor that we find in the cytoplasm in a cross‐striated pattern and at a high level in the nuclear envelope zone. Finally, we show that the blockade of these IP3‐induced calcium signals by 2‐APB prevents the AChRn decrease induced by thrombin. Our results thus demonstrate that thrombin downregulates AChR expression by activating PAR‐1 and that this effect is mediated via an IP3 signaling pathway. © 2003 Wiley‐Liss, Inc.
DOI：
10.1073/pnas.95.12.6642
发表时间：
1998-06-09
影响因子：
11.1
作者：
Xu, WF;Andersen, H;Foster, DC
通讯作者：
Foster, DC
凝血酶受体通过体外蛋白激酶 C 激活介导功能活动依赖性神经肌肉突触减少。
DOI：
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发表时间：
1999
期刊：
Journal of neurobiology
影响因子：
--
作者：
Jia,M;Li,M;Dunlap,V;Nelson,PG
通讯作者：
Nelson,PG
小鼠凝血酶原缺乏引起的不完全胚胎致死和致命性新生儿出血。
DOI：
10.1073/pnas.95.13.7603
发表时间：
1998
影响因子：
11.1
作者：
Xue,J;Wu,Q;Westfield,LA;Tuley,EA;Lu,D;Zhang,Q;Shim,K;Zheng,X;Sadler,JE
通讯作者：
Sadler,JE