Local activation of focal adhesion kinase orchestrates the positioning of presynaptic scaffold proteins and Ca2+ signalling to control glucose-dependent insulin secretion
Dillon Jevon,
Kylie Deng,
Nicole Hallahan,
Krish Kumar,
Jason Tong,
Wan Jun Gan,
Clara Tran,
Marcela Bilek,
Peter Thorn
Affiliations
Dillon Jevon
Charles Perkins Centre, School of Medical Sciences, University of Sydney, Sydney, Australia
Charles Perkins Centre, School of Medical Sciences, University of Sydney, Sydney, Australia
Wan Jun Gan
Charles Perkins Centre, School of Medical Sciences, University of Sydney, Sydney, Australia
Clara Tran
School of Physics, University of Sydney, Sydney, Australia
Marcela Bilek
School of Physics, University of Sydney, Sydney, Australia; School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, Sydney, Australia; Sydney Nanoscience Institute, University of Sydney, Sydney, Australia
A developing understanding suggests that spatial compartmentalisation in pancreatic β cells is critical in controlling insulin secretion. To investigate the mechanisms, we have developed live-cell subcellular imaging methods using the mouse organotypic pancreatic slice. We demonstrate that the organotypic pancreatic slice, when compared with isolated islets, preserves intact β-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 (FAK), in regulating β cells. Integrins and FAK are exclusively activated at the β-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 FAK orchestrates the final steps of glucose-dependent insulin secretion within the restricted domain where β-cell contact the islet capillaries.
