Investigating heterogeneity of intracellular calcium dynamics in anterior pituitary lactotrophs using a combined modelling/experimental approach

摘要

Cell responses are commonly heterogeneous, even within a subpopulation. Here we investigate the source of heterogeneity in the Ca²⁺ response of anterior pituitary lactotrophs to a Ca²⁺ mobilization agonist, thyrotropin-releasing hormone. This response is characterized by a sharp increase of cytosolic Ca²⁺ concentration, due to mobilization 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 condition. We introduce a method that uses the information provided by a mathematical model to characterize the source of heterogeneity. This method compares scatter plots of features of the Ca²⁺ response obtained experimentally to those made from the mathematical model. The model scatter plots reflect random variation of parameters over different ranges, and matching 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 TRH in lactotrophs. This technique is applicable to any situation in which the heterogeneous biological response is described by a mathematical model.