CONICET | Buscador de Institutos y Recursos Humanos

Sensing extracellular changes initiates signal transduction and is the first stage ofcellular decision-making. Ligand binding to cell membrane receptors is a key event inthose sensing stages. It is rarely certain whether cellular responses are related to initialchanges in receptor binding or to the level of receptor binding achieved at some latertime, but it is likely that the dynamics of receptor/ligand binding contributes significantlyto the dynamics of the response. Particularly, certain properties of the sensing steps areusually characterized in equilibrium, like the value of half-maximal effectiveconcentration, the dynamic range, and the Hill coefficient. However, if the time constantof downstream signal transduction steps is shorter than that of ligand-receptor binding,those properties should be evaluated in pre-equilibrium.Using a simple monovalent binding model, a two-state binding model, and two limitingcases of this last one in which only one receptor form can bind or release ligand, westudied the mentioned properties in pre-equilibrium, finding that the dynamic range of asignaling pathway can be modulated (shifted or enlarged) by using pre-equilibriumproperties of the ligand-receptor reaction. We combined analytical tools when possible,with computational modeling and parameter space exploration. We have also analyzedcooperativity effects in membrane receptors with two binding sites. It is known that, inequilibrium, is not possible to distinguish between negative cooperativity andindependent sites. Recent works showed that pre-equilibrium information may allow todo so. We have studied in detail the dynamics of cooperativity effects in order to findmeasurable estimators for discrimination between these two microscopic scenarios.* Equal contributions