Regulation of the Molecular Shuttle Service: A Multiscale Model of Aquaporin 2 Recycling

Abstract

The response of cells to their environment is driven by a variety of proteins and messenger molecules. In eukaryotes their distribution, which is regulated by a vesicular transport system, is important for a tight cellular response. The recycling of aquaporin 2 between membrane and storage region is a crucial part of the body water homeostasis 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. To achieve this we developed a multiscale computational framework for the modeling and simulation of cellular systems. The analysis of the system rationalises 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.