Computer simulation of calcium transport mechanisms: Application to the intestinal absorption of calcium

Abstract

Computer simulations of transcellular transport across the intestinal epithelium were carried out using the simulation program SPICE. This program was originally designed to analyze electrical networks, but it is easily applied to many biological problems. The biological transport mechanisms which were successfully modeled by SPICE included: (1) the negative-feedback entry of calcium at the brush-border membrane; (2) a saturable exit of calcium at the baso-lateral membrane; (3) the binding of calcium to calbindin within the cell cytosol; and (4) the diffusion of both free calcium and calcium bound to calbindin through the cytosol from the apical aspect to the basal aspect of the enterocytes. A description of the SPICE network for each of these mechanisms is given, together with the simulated results of the transport mechanisms studied in isolation. This procedure allowed the validation of the individual transport mechanisms for situations in which closed-form solutions to the network were possible. The individual transport mechanisms were then assembled into a network which simulated transport across the epithelial layer. The simulations were conducted with or without calbindin. The results show that the diffusable calcium-binding protein, calbindin, increases the overall net calcium transport by increasing the net flux across the brush-border, cytosol, and baso-lateral membrane. Calbindin reduced the free calcium immediately adjacent to the brush-border membrane, thereby enhancing entry of calcium into the cell by relieving the negative feedback inhibition of calcium entry. Calbindin enhanced the diffusion of calcium through the cytosol by physically carrying the calcium through this compartment. Calbindin increased the free calcium adjacent to the baso-lateral Ca-ATPase extrusion mechanism, thereby providing substrate-level activation of calcium efflux into the blood side of the epithelium. The main advantage of the SPICE simulation program is its relative simplicity. The structure of the SPICE network maps readily onto the structure of the biological system, which clarifies the SPICE network as an analogue of the biological system.