Submembrane liprin-α1 clusters spatially localize insulin granule fusion.

Abstract

Insulin granule fusion in pancreatic β cells localizes to where they contact the ECM of the islet capillaries. The mechanism(s) underpinning localization are unclear. Using glucose or high K+ stimulation or the global uncaging of Ca2+, we show granule fusion consistently focused to the β cell-ECM interface, suggesting a specific localization mechanism. We tested for the involvement of liprin-α1, a scaffold protein enriched at the β cell-ECM interface. Liprin-α1 knockdown did not affect high K+-stimulated insulin secretion but did impair localization of exocytosis. Liprin-α1 knockdown impaired glucose-induced insulin secretion with evidence that the C-terminal of liprin-α1 positions liprin-α1 in clusters at the β cell-ECM interface. Liprin-α1 cluster size and number are regulated by glucose, and exocytosis is spatially coupled with the clusters. Immunoprecipitation and mass spectrometry characterized a liprin-α1 interactome, including β2-syntrophin, an insulin granule-linked protein. We conclude that liprin-α1 is part of a complex that is regulated by glucose and locally targets insulin granules to the β cell-ECM interface.