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Feedback regulation of insulin secretion by extended synaptotagmin-1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2019 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 33, no 4, p. 4716-4728Article in journal (Refereed) Published
Abstract [en]

Endoplasmic reticulum (ER)-plasma membrane (PM) contacts are dynamic structures with important roles in the regulation of calcium (Ca2+) and lipid homeostasis. The extended synaptotagmins (E-Syts) are ER-localized lipid transport proteins that interact with PM phosphatidylinositol 4,5-bisphosphate in a Ca2+-dependent manner. E-Syts bidirectionally transfer glycerolipids, including diacylglycerol (DAG), between the 2 juxtaposed membranes, but the biologic significance of this transport is still unclear. Using insulin-secreting cells and live-cell imaging, we now show that Ca2+-triggered exocytosis of insulin granules is followed, in sequence, by PM DAG formation and E-Syt1 recruitment. E-Syt1 counteracted the depolarization-induced DAG formation through a mechanism that required both voltage-dependent Ca2+ influx and Ca2+ release from the ER. E-Syt1 knockdown resulted in prolonged accumulation of DAG in the PM, resulting in increased glucose-stimulated insulin secretion. We conclude that Ca2+-triggered exocytosis is temporally coupled to Ca2+-triggered E-Syt1 PM recruitment and removal of DAG to negatively regulate the same process.

Place, publisher, year, edition, pages
2019. Vol. 33, no 4, p. 4716-4728
Keywords [en]
Ca2+, beta-cell, membrane contact sites, TMEM24, PKC
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-382253DOI: 10.1096/fj.201801878RISI: 000462888500007PubMedID: 30589572OAI: oai:DiVA.org:uu-382253DiVA, id: diva2:1313526
Funder
Swedish Research CouncilAvailable from: 2019-05-03 Created: 2019-05-03 Last updated: 2019-05-03Bibliographically approved

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Xie, BeichenNguyen, Phuoc MyIdevall-Hagren, Olof

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