环磷酸腺苷（cAMP）诱导的蛋白激酶A和p190B RhoGAP激活介导了质膜上TC10活性的下调以及神经突生长。

cAMP-induced activation of protein kinase A and p190B RhoGAP mediates down-regulation of TC10 activity at the plasma membrane and neurite outgrowth.

作者信息

Koinuma Shingo, Takeuchi Kohei, Wada Naoyuki, Nakamura Takeshi

机构信息

Division of Biosignaling, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.

Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.

出版信息

Genes Cells. 2017 Nov;22(11):953-967. doi: 10.1111/gtc.12538. Epub 2017 Oct 26.

DOI:10.1111/gtc.12538

Abstract

Cyclic AMP plays a pivotal role in neurite growth. During outgrowth, a trafficking system supplies membrane at growth cones. However, the cAMP-induced signaling leading to the regulation of membrane trafficking remains unknown. TC10 is a Rho family GTPase that is essential for specific types of vesicular trafficking. Recent studies have shown a role of TC10 in neurite growth in NGF-treated PC12 cells. Here, we investigated a mechanical linkage between cAMP and TC10 in neuritogenesis. Plasmalemmal TC10 activity decreased abruptly after cAMP addition in neuronal cells. TC10 was locally inactivated at extending neurite tips in cAMP-treated PC12 cells. TC10 depletion led to a decrease in cAMP-induced neurite outgrowth. Constitutively active TC10 could not rescue this growth reduction, supporting our model for a role of GTP hydrolysis of TC10 in neuritogenesis by accelerating vesicle fusion. The cAMP-induced TC10 inactivation was mediated by PKA. Considering cAMP-induced RhoA inactivation, we found that p190B, but not p190A, mediated inactivation of TC10 and RhoA. Upon cAMP treatment, p190B was recruited to the plasma membrane. STEF depletion and Rac1-N17 expression reduced cAMP-induced TC10 inactivation. Together, the PKA-STEF-Rac1-p190B pathway leading to inactivation of TC10 and RhoA at the plasma membrane plays an important role in cAMP-induced neurite outgrowth.

摘要

环磷酸腺苷（cAMP）在神经突生长中起关键作用。在神经突生长过程中，一个运输系统在生长锥处提供膜。然而，cAMP诱导的导致膜运输调节的信号传导仍不清楚。TC10是一种Rho家族GTP酶，对特定类型的囊泡运输至关重要。最近的研究表明TC10在神经生长因子（NGF）处理的PC12细胞的神经突生长中发挥作用。在此，我们研究了cAMP与TC10在神经突形成中的机械联系。在神经元细胞中添加cAMP后，质膜上的TC10活性突然下降。在cAMP处理的PC12细胞中，TC10在延伸的神经突尖端局部失活。TC10缺失导致cAMP诱导的神经突生长减少。组成型活性TC10无法挽救这种生长减少，这支持了我们关于TC10的GTP水解通过加速囊泡融合在神经突形成中起作用的模型。cAMP诱导的TC10失活由蛋白激酶A（PKA）介导。考虑到cAMP诱导的RhoA失活，我们发现p190B而非p190A介导了TC10和RhoA的失活。经cAMP处理后，p190B被募集到质膜。STEF缺失和Rac1 - N17表达降低了cAMP诱导的TC10失活。总之，导致TC10和RhoA在质膜失活的PKA - STEF - Rac1 - p190B途径在cAMP诱导的神经突生长中起重要作用。