Investigating Heterogeneity of Intracellular Calcium Dynamics in Anterior Pituitary Lactotrophs Using a Combined Modelling/Experimental Approach

Maurizio Tomaiuolo, Richard Bertram, Arturo E. Gonzalez-Iglesias, Joel Tabak

Cell responses are commonly heterogeneous, even within a subpopulation. In the present study, we investigate the source of heterogeneity in the calcium response of anterior pituitary lactotrophs to a calcium mobilisation agonist, thyrotrophin-releasing hormone. This response is characterised by a sharp increase of cytosolic calcium concentration as a result of mobilisation of calcium from intracellular stores, followed by a decrease to an elevated plateau level that results from calcium influx. We focus on heterogeneity of the evoked calcium spike under extracellular calcium free conditions. We introduce a method that uses the information provided by a mathematical model to characterise the source of heterogeneity. This method compares scatter plots of features of the calcium response obtained experimentally with those made from the mathematical model. The model scatter plots reflect random variation of parameters over different ranges, and matching the experimental and model scatter plots allows us to predict which parameters are most variable. We find that a large degree of variation in calcium influx is a likely key contributor to the heterogeneity of calcium responses to thyrotrophin-releasing hormone in lactotrophs. This technique is applicable to any situation in which the heterogeneous biological response is described by a mathematical model.