Organization and dynamics of the cortical complexes controlling insulin secretion in β-cells

Author:

Noordstra Ivar12,van den Berg Cyntha M.1,Boot Fransje W. J.3,Katrukha Eugene A.1,Yu Ka Lou1ORCID,Tas Roderick P.1,Portegies Sybren1,Viergever Bastiaan J.1ORCID,de Graaff Esther1ORCID,Hoogenraad Casper C.1ORCID,de Koning Eelco J. P.3,Carlotti Françoise3,Kapitein Lukas C.1ORCID,Akhmanova Anna1ORCID

Affiliation:

1. Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands

2. Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia

3. Department of Internal Medicine, Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

Abstract

ABSTRACT Insulin secretion in pancreatic β-cells is regulated by cortical complexes that are enriched at the sites of adhesion to extracellular matrix facing the vasculature. Many components of these complexes, including bassoon, RIM, ELKS and liprins, are shared with neuronal synapses. Here, we show that insulin secretion sites also contain the non-neuronal proteins LL5β (also known as PHLDB2) and KANK1, which, in migrating cells, organize exocytotic machinery in the vicinity of integrin-based adhesions. Depletion of LL5β or focal adhesion disassembly triggered by myosin II inhibition perturbed the clustering of secretory complexes and attenuated the first wave of insulin release. Although previous analyses in vitro and in neurons have suggested that secretory machinery might assemble through liquid–liquid phase separation, analysis of endogenously labeled ELKS in pancreatic islets indicated that its dynamics is inconsistent with such a scenario. Instead, fluorescence recovery after photobleaching and single-molecule imaging showed that ELKS turnover is driven by binding and unbinding to low-mobility scaffolds. Both the scaffold movements and ELKS exchange were stimulated by glucose treatment. Our findings help to explain how integrin-based adhesions control spatial organization of glucose-stimulated insulin release.

Funder

ZonMw

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Human Frontier Science Program

European Foundation for the Study of Diabetes

European Molecular Biology Organization

Universiteit Utrecht

Publisher

The Company of Biologists

Subject

Cell Biology

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