The Dynamics of Calcium Signaling in Beta Cells—A Discussion on the Comparison of Experimental and Modelling Data

Abstract

The stimulus–secretion coupling of the pancreatic beta cell is particularly complex, as it integrates the availability of glucose and other nutrients with the neuronal and hormonal input to generate rates of insulin secretion that are appropriate for the entire organism. It is beyond dispute however, that the cytosolic Ca2+ concentration plays a particularly prominent role in this process, as it not only triggers the fusion of insulin granules with the plasma membrane, but also regulates the metabolism of nutrient secretagogues and affects the function of ion channels and transporters. In order to obtain a better understanding of the interdependence of these processes and, ultimately, of the entire beta cell as a working system, models have been developed based on a set of nonlinear ordinary differential equations, and were tested and parametrized on a limited set of experiments. In the present investigation, we have used a recently published version of the beta cell model to test its ability to describe further measurements from our own experimentation and from the literature. The sensitivity of the parameters is quantified and discussed; furthermore, the possible influence of the measuring technique is taken into account. The model proved to be powerful in correctly describing the depolarization pattern in response to glucose and the reaction of the cytosolic Ca2+ concentration to stepwise increases of the extracellular K+ concentration. Additionally, the membrane potential during a KATP channel block combined with a high extracellular K+ concentration could be reproduced. In some cases, however, a slight change of a single parameter led to an abrupt change in the cellular response, such as the generation of a Ca2+ oscillation with high amplitude and high frequency. This raises the question as to whether the beta cell may be a partially unstable system or whether further developments in modeling are needed to achieve a generally valid description of the stimulus–secretion coupling of the beta cell.

Data‐driven stochastic model for quantifying the interplay between amyloid‐beta and calcium levels in Alzheimer's disease

“…$$$ A\beta $$$ may alter $$$ {Ca}^{+2} $$$ signaling by numerous methods, including boosting $$$ {Ca}^{+2} $$$ inflow from the extracellular area and stimulating $$$ {Ca}^{+2} $$$ release from intracellular repositories within the brain [24, 25]. Moreover, growing evidence suggests that there is a positive loop between $$$ {Ca}^{+2} $$$ and $$$ A\beta $$$ levels [13, 26, 27]. We know by now, for example, that the persistent high concentration of $$$ {Ca}^{+2} $$$ is favorable to the formation of $$$ A\beta $$$ in rat cortical neurons by imitating $$$ A\gamma $$$ secretase activity, which is crucial for the breakdown of amyloid precursor protein (APP) [13, 28].…”