Role of the active zone protein, ELKS, in insulin secretion from pancreatic β-cells

Background: Insulin is stored within large dense-core granules in pancreatic beta (beta)-cells and is released by Ca2+-triggered exocytosis with increasing blood glucose levels. Polarized and targeted secretion of insulin from beta-cells in pancreatic islets into the vasculature has been proposed; however, the mechanisms related to cellular and molecular localization remain largely unknown. Within nerve terminals, the Ca-2(+)-dependent release of a polarized transmitter is limited to the active zone, a highly specialized area of the presynaptic membrane. Several active zone-specific proteins have been characterized; among them, the CAST/ELKS protein family members have the ability to form large protein complexes with other active zone proteins to control the structure and function of the active zone for tight regulation of neurotransmitter release. Notably, ELKS but not CAST is also expressed in beta-cells, implying that ELKS may be involved in polarized insulin secretion from beta-cells. Scope of review: This review provides an overview of the current findings regarding the role(s) of ELKS and other active zone proteins in beta-cells and focuses on the molecular mechanism underlying ELKS regulation within polarized insulin secretion from islets. Major conclusions: ELKS localizes at the vascular-facing plasma membrane of beta-cells in mouse pancreatic islets. ELKS forms a potent insulin secretion complex with L-type voltage-dependent Ca2+ channels on the vascular-facing plasma membrane of beta-cells, enabling polarized Ca2+ influx and first-phase insulin secretion from islets. This model provides novel insights into the functional polarity observed during insulin secretion from beta-cells within islets at the molecular level. This active zone-like region formed by ELKS at the vascular side of the plasma membrane is essential for coordinating physiological insulin secretion and may be disrupted in diabetes. (C) 2019 Published by Elsevier GmbH.