The supply of red blood cells in mammals is controlled by the cytokine erythropoietin (EPO). In physiological situations, the concentration of EPO can change by 1000-fold. Becker et al. used a combination of mathematical modeling and experimental analysis to discern how cells can maintain a linear response to such a broad range of EPO concentrations. Critical features included internalization of EPO-bound receptors and subsequent degradation of the EPO ligand. Replenishment of receptors at the cell surface required a large supply of EPO receptors maintained in reserve inside the cell. These mechanisms allow cells to experience large increases in EPO concentration without becoming refractory to further stimulation.
V. Becker, M. Schilling, J. Bachmann, U. Baumann, A. Raue, T. Maiwald, J. Timmer, U. Klingmüller, Covering a broad dynamic range: Information processing at the erythropoietin receptor. Science 328, 1404–1408 (2010). [Abstract] [Full Text]