Seminar by Juan Pablo Di Bella

Analysis of transient properties in Dose-Response functions

Juan Pablo Di Bella, University of Buenos Aires

Sensing extracellular changes initiates signal transduction and is the first stage of cellular decision-making. Ligand binding to cell membrane receptors is a key event in those sensing stages. It is rarely certain whether cellular responses are related to initial changes in receptor binding or to the level of receptor binding achieved at some later time, but it is likely that the dynamics of receptor/ligand binding contributes significantly to the dynamics of the response. Particularly, certain properties of the sensing steps are usually characterized in equilibrium, like the value of half-maximal effective concentration, the dynamic range, and the Hill coefficient. However, if the time constant of downstream signal transduction steps is shorter than that of ligand-receptor binding, those properties should be evaluated in pre-equilibrium. We explored how the main features of these properties, are being limited when considering different signaling topologies. Two models of receptor activation, a covalent modification cycle, and a transcriptional model are considered here, we explored their specific features and also the effect when we couple some of these modules.

Our results imply that pre-equilibrium sensing is possible depending on the relation of binding and activation rates. When binding rates are slower than activation rates, the system can sense high dose concentrations on pre-equilibrium. Conversely, when binding is faster than activation, pre-equilibrium sensing properties remains similar than steady state properties. Moreover, when the time scales are similar, pre-equilibrium sensing is possible but with certain limitations, depending on the time constant and the ligand concentration involved on the downstream process.