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

Cell responses are commonly heterogeneous, even within a subpopulation. In the present study, we investigate the source of heterogeneity in the Ca2+ response of anterior pituitary lactotrophs to a Ca2+ mobilisation agonist, thyrotrophin‐releasing hormone. This response is characterised by a sharp increase of cytosolic Ca2+ concentration as a result of mobilisation of Ca2+ from intracellular stores, followed by a decrease to an elevated plateau level that results from Ca2+ influx. We focus on heterogeneity of the evoked Ca2+ spike under extracellular Ca2+ 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 Ca2+ 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 Ca2+ efflux is a likely key contributor to the heterogeneity of Ca2+ 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.