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

ABSTRACT: In pancreatic ?-cells, intracellular Ca²⁺ ([Ca²⁺]_i) acts as a trigger for secretion of glucagon, a hormone that plays a key role in blood glucose homeostasis. Intracellular Ca²⁺ 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 ?-cells, the global Ca²⁺ response to lowering external glucose occurs in the form of oscillations that are much slower than electrical activity. These Ca²⁺ oscillations are highly variable as far as inter-spike intervals, shapes and amplitudes are concerned. Such observations suggest that Ca²⁺ dynamics in ?-cells are much influenced by noise. Actually, each Ca²⁺ increase corresponds to multiple cycles of opening/closing of voltage gated Ca²⁺ 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 Ca²⁺ oscillations in ?-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 ?-cells electrical activity (Diderichsen and Göpel, 2006) to take Ca²⁺ 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 Ca²⁺ oscillations with a time scale of a few tens of seconds. However, when taking into account the intimate relation between Ca²⁺ and ATP changes together with the intrinsic noise at the level of the K_ATP channels, simulations displayed Ca²⁺ oscillations that are compatible with experimental observations. We analyzed the detailed mechanism and used computational simulations to identify the factors that can affect Ca²⁺ oscillations in ?-cells.

SUBMITTER: Gonzalez-Velez V 

PROVIDER: S-EPMC7705205 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature