Modelling Electrical Bursting and Calcium Waves in Pancreatic beta-Cells

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9411244 Chay In pancreatic beta cells the ion channels, the phosphatidylinositol signal, and the receptor controlled adenylate-cyclase pathway are intricately interwoven so as to control insulin release. Modelling studies will certainly help clarify the main events that take place in these complex interwoven phenomena. The goal of this research is to formulate a mathematical model that explains the interplay between the ion channels, receptors, intracellular calcium stores, and intercellular calcium wave propagation in pancreatic beta-cells in the islet of Langerhans. This project has two major goals. The first is to incorporate recent patch-clamp experiments and spectrophotometric data into the mathematical bursting model developed by this group over a number of years so as to link the membrane oscillator model with a receptor-controlled calcium oscillator model. With this refined model, the role each channel plays in triggering the bursting and intracellular calcium oscillations will be quantified, and the coordination of release of calcium from internal stores with the influx of extracellular calcium will be investigated. In addition, how electrical activity and intracellular calcium concentration change in response to intra-islet hormones and neurotransmitters released from sympathetic and parasympathetic fibers will be explored. The second major goal is to develop user-friendly software which simulates beta cell electrophysiology and intracellular calcium dynamics for researchers studying excitable cells as well as for teachers in the classroom. %%% Insulin is a hormone that plays a key role in regulating the level of sugar in blood. Insulin is produced in specialized cells of the pancreas, the beta cells. Beta cells release insulin in response to a number of external stimuli such as increases in the blood concentration of the simple sugar, glucose, as well as certain neurotransmitters and some other hormones. Understanding the chain of events between the cell's detection of these chemical stimuli and the release of insulin is the goal of much research in many laboratories. It is known that the chain of events involves bursts of electrical activity at the beta cell membrane and oscillations of the cell's internal calcium levels. Each of these is caused by certain biochemical changes in the cell and results in other biochemical changes. The goal of this research is to develop detailed mathematical models that will aid in clarifying the relationships among these complex and interdependent sequences of biochemical and biophysical events. Mathematical models are useful not only in helping to interpret existing experimental data but also in suggesting further experiments that ultimately will allow us to understand the transduction of the extracellular signals that stimulate pancreatic cells to release insulin. A second goal of this project is to develop user-friendly software that will facilitate studies by other researchers and students interested in similar biophysical and biochemical phenomena. ***