STIM1 regulates pancreatic ß-cell behaviour: A modelling study.

ABSTRACT

Pancreatic ß-cells are equipped with the molecular machinery allowing them to respond to high glucose levels in the form of electrical activity and Ca2+ oscillations. These oscillations drive insulin secretion. Two key ionic mechanisms involved in this response are the Store-Operated Current and the current through ATP-dependent K+ channels. Both currents have been shown to be regulated by the protein STIM1, but this dual regulation by STIM1 has not been studied before. In this paper, we use mathematical modelling to gain insight into the role of STIM1 in the ß-cell response. We extended a previous ß-cell model to include the dynamics of STIM1 and described the dependence of the ATP-dependent K+ current on STIM1. Our simulations suggest that the total concentration of STIM1 modifies the bursting frequency, the burst duration and the intracellular Ca2+ levels. These results are in good agreement with experimental reports, and the contribution of the studied currents to electrical activity and Ca2+ dynamics is discussed. The model predicts that in the absence of STIM1 the excitability of the plasma membrane increases and that the glucose threshold for electrical activity is shifted to lower concentrations. These computational predictions may be related to impaired insulin secretion under conditions of reduced STIM1 in the diabetic state.