Intracellular ion concentration and cation transporter activities are important determinants of many fundamental physiological parameters, including cell turgor, plasma membrane potential and intracellular pH. In order to maintain these parameters within physiological ranges despite external perturbations, cells regulate their transporter activities through both post-translational modifications and gene regulation.
In this thesis, the ion regulations in two model fungal species, Saccharomyces cerevisiae and Aspergillus nidulans, are investigated. We use a mathematical modelling approach to gain a quantitative understanding of the impact of collective transporter activities on the intracellular cation concentrations and the cellular adaptation processes. This thesis is mainly composed of two parts: 1) A biophysical and mathematical model is built for the cation transporters and their regulatory proteins to describe the temporal changes of cell volume, intracellular pH and cation concentrations during hyper-osmotic stress, ionic stress and alkaline pH stress in S. cerevisiae. 2) Four models are built for the activation of the alkaline pH responsive transcription factor, PacC, in A. nidulans, based on competing hypotheses.
The integrated model in the first part shows that calcineurin activation in response to stress conditions results in a rapid and transient decrease of membrane potential, which we speculate is an important strategy for the cell to respond to unknown external ionic perturbations. The model also confirms the importance of Hog1p phosphorylation on Nha1p and Tok1p for immediate adaptation to salt stress and predicted that activated Hog1p down-regulates Tok1p activity. In alkaline stress conditions, the induction of Ena1p expression results in increased membrane potential. This model provides a theoretical framework for the study of ion homeostasis in stress conditions, the understanding of drug effects, such as FK506. And since the membrane potential is an important determinant of drug uptake, the
model is well suited for the drug development. In the second part of the thesis, results from those competing models for PacC activation show significant difference for the pacC904 mutant strain and suggests that further experiments on this strain would be able to uncover the role of the intermediate form, PacC53, plays in the activation process.