%0 Journal Article %A Simon Rogers %A Virgilio L. Lew %T I. A novel multiplatform model of human red blood cell homeostasis applied to investigate the mechanisms behind the multiple effects of elevated [Ca2+]i %D 2020 %R 10.1101/2020.03.07.981779 %J bioRxiv %P 2020.03.07.981779 %X Wild-type and mutant forms of PIEZO1 and Gardos channels (KCNN4) play important roles in physiological red blood cell (RBC) senescence, and within a group of inherited haemolytic anaemias characterized by RBC dehydration resulting from elevated [Ca2+]i. The first purpose of this paper is to introduce a new multiplatform JAVA-based mathematical-computational model of RBC homeostasis for investigating the dynamics of changes in RBC homeostasis in health and disease. The second purpose is to apply the model to investigate in depth the multiple effects associated with Ca2+-induced potassium permeabilization. This investigation is a necessary preliminary for the application of the model to elucidate the mechanisms behind the changes in RBC homeostasis during capillary transits and over the full circulatory lifespan of the cells in normal and sickle cells, the subject of the next two papers of this series. Using the red cell model (RCM), framed within a detailed tutorial context, we design and run in silico representations of experimental protocols to study global RBC responses to K+ permeabilization covering a wide range of experimental, physiological and pathological conditions. Model outputs report the evolution in time of all the homeostatic variables in the system allowing, for the first time, a detailed and comprehensive account of the complex processes shaping global cell responses. Analysis of the results explained the mechanisms by which the entangled operation of multiple RBC components link Ca2+-induced cell dehydration and protein crowding to cell acidification and to the generation of hypertonic, alkaline effluents. Open access to the JAVA model in a GitHub repository, together with the tutorial primed for the current investigation pave the way for researchers and clinicians to apply the model on many different aspects of RBC physiology and pathology. %U https://www.biorxiv.org/content/biorxiv/early/2020/03/23/2020.03.07.981779.full.pdf