Calcium Oscillations in Pancreatic α-cells Rely on Noise and ATP-Driven Changes in Membrane Electrical Activity

In pancreatic α-cells, intracellular Ca(2+) ([Ca(2+)](i)) acts as a trigger for secretion of glucagon, a hormone that plays a key role in blood glucose homeostasis. Intracellular Ca(2+) dynamics in these cells are governed by the electrical activity of voltage-gated ion channels, among which ATP-sensitive K(+) (K(ATP)) channels play a crucial role. In the majority of α-cells, the global Ca(2+) response to lowering external glucose occurs in the form of oscillations that are much slower than electrical activity. These Ca(2+) oscillations are highly variable as far as inter-spike intervals, shapes and amplitudes are concerned. Such observations suggest that Ca(2+) dynamics in α-cells are much influenced by noise. Actually, each Ca(2+) increase corresponds to multiple cycles of opening/closing of voltage gated Ca(2+) channels that abruptly become silent, before the occurrence of another burst of activity a few tens of seconds later. The mechanism responsible for this intermittent activity is currently unknown. In this work, we used computational modeling to investigate the mechanism of cytosolic Ca(2+) oscillations in α-cells. Given the limited population of K(ATP) channels in this cell type, we hypothesized that the stochastic activity of these channels could play a key role in the sporadic character of the action potentials. To test this assumption, we extended a previously proposed model of the α-cells electrical activity (Diderichsen and Göpel, 2006) to take Ca(2+) dynamics into account. Including molecular noise on the basis of a Langevin type description as well as realistic dynamics of opening and closing of K(ATP) channels, we found that stochasticity at the level of the activity of this channel is on its own not able to produce Ca(2+) oscillations with a time scale of a few tens of seconds. However, when taking into account the intimate relation between Ca(2+) and ATP changes together with the intrinsic noise at the level of the K(ATP) channels, simulations displayed Ca(2+) oscillations that are compatible with experimental observations. We analyzed the detailed mechanism and used computational simulations to identify the factors that can affect Ca(2+) oscillations in α-cells.