Guiding principles for modelling cellular transport homeostasis

Cellular transport homeostasis evolved as a universal strategy linking the dynamic interactions between membrane transport, metabolism and biosynthesis in all cells. The entangled nature of these interactions, together with the effects from additional processes influencing homeostatic variables generate complexities that render intuition an unreliable interpreter and predictor of cell responses often prompting for modelling help. The main variables in transport homeostasis are membrane potentials, cell volume, ion and neutral solute fluxes through active and passive membrane transporters, cytoplasmic amounts and concentrations of soluble ions and neutral solutes, charge and concentrations of impermeant cytoplasmic solutes, charge and osmotic coefficient of cytoplasmic proteins, and cytoplasmic H⁺, Ca²⁺ and Mg²⁺ buffering. Models of cellular transport homeostasis developed to explain puzzling, unexpected or conflicting observations in epithelia, red blood cells, malaria-infected red blood cells, reticulocytes, sickle cells, and plant guard cells proved essential for explaining underlying mechanisms in many experimental, physiological and pathological contexts and for elucidating conflicts greatly expanding our knowledge of the cell systems investigated thus far. The transport homeostasis loop is an ancient circuit that preserves cellular integrity. In this cycle, metabolic ATP powers families of membrane pumps that sustain ionic gradients across plasma membranes. These gradients act as secondary sources of energy for the passive transport of ions through channels and through ion-coupled solute carriers. These, in turn, supply the substrates for metabolic ATP production and for the biosynthesis of proteins, lipids, RNA and DNA that replace decayed membrane transporters, closing the transport homeostasis loop. This review outlines the foundational principles applied when developing models of this dynamic circuit and of the achievements resulting from their application in different cell types.