Biotechnology Center (BIOTEC), TU Dresden, Dresden, 01307, Germany.
University of Applied Sciences Mittweida, Mittweida, 09648, Germany.
NPJ Syst Biol Appl. 2022 May 9;8(1):16. doi: 10.1038/s41540-022-00223-y.
The response of cells to their environment is driven by a variety of proteins and messenger molecules. In eukaryotes, their distribution and location in the cell are regulated by the vesicular transport system. The transport of aquaporin 2 between membrane and storage region is a crucial part of the water reabsorption in renal principal cells, and its malfunction can lead to Diabetes insipidus. To understand the regulation of this system, we aggregated pathways and mechanisms from literature and derived three models in a hypothesis-driven approach. Furthermore, we combined the models to a single system to gain insight into key regulatory mechanisms of Aquaporin 2 recycling. To achieve this, we developed a multiscale computational framework for the modeling and simulation of cellular systems. The analysis of the system rationalizes that the compartmentalization of cAMP in renal principal cells is a result of the protein kinase A signalosome and can only occur if specific cellular components are observed in conjunction. Endocytotic and exocytotic processes are inherently connected and can be regulated by the same protein kinase A signal.
细胞对其环境的反应是由各种蛋白质和信使分子驱动的。在真核生物中，它们在细胞中的分布和位置受囊泡运输系统的调节。水通道蛋白 2 在膜和储存区域之间的运输是肾主细胞中水分重吸收的关键部分，其功能障碍可导致尿崩症。为了理解这个系统的调节机制，我们从文献中收集了途径和机制，并在假设驱动的方法中得出了三个模型。此外，我们将这些模型结合起来形成一个单一的系统，以深入了解水通道蛋白 2 回收的关键调节机制。为了实现这一目标，我们开发了一个用于细胞系统建模和模拟的多尺度计算框架。对系统的分析合理化了 cAMP 在肾主细胞中的区室化是蛋白激酶 A 信号体的结果，只有在观察到特定的细胞成分时才能发生。内吞作用和胞吐作用本质上是相互连接的，可以被相同的蛋白激酶 A 信号调节。
