Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ channel function to control glucose dependent insulin secretion.

Abstract

A developing understanding suggests that spatial compartmentalisation of components the glucose stimulus-secretion pathway in pancreatic {beta} cells are critical in controlling insulin secretion. To investigate the mechanisms, we have developed live-cell sub-cellular imaging methods using the organotypic pancreatic slice. We demonstrate that the organotypic pancreatic slice, when compared with isolated islets, preserves intact {beta} cell structure, and enhances glucose dependent Ca2+ responses and insulin secretion. Using the slice technique, we have discovered the essential role of local activation of integrins and the downstream component, focal adhesion kinase, in regulating {beta} cells. Integrins and focal adhesion kinase are exclusively activated at the {beta} cell capillary interface and using in situ and in vitro models we show their activation both positions presynaptic scaffold proteins, like ELKS and liprin, and regulates glucose dependent Ca2+ responses and insulin secretion. We conclude that focal adhesion kinase orchestrates the final steps of glucose dependent insulin secretion within the restricted domain where {beta} cells contact the islet capillaries.