Journal
FASEB JOURNAL
Volume 33, Issue 4, Pages 4716-4728Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201801878R
Keywords
Ca2+; beta-cell; membrane contact sites; TMEM24; PKC
Categories
Funding
- Swedish Research Council
- Goran Gustafsson Foundation
- Malin and Lennart Philipson Foundation
- Excellence of Diabetes Research in Sweden
- Ake Wiberg Foundation
- Novo-Nordisk Foundation
- Magnus Bergwall Foundation
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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.
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