Feedback regulation of insulin secretion by extended synaptotagmin‐1

Abstract

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.—Xie, B., Nguyen, P. M., Idevall‐Hagren, O. Feedback regulation of insulin secretion by extended synaptotagmin‐1. FASEB J. 33, 4716–4728 (2019). http://www.fasebj.org

Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress

“…Despite the difficulty of identifying the specific lipids preferentially transported by the SMP domain of E-Syts, analysis of cells lacking all three E-Syts supports the hypothesis that the E-Syts function in vivo is to clear DAG formed at the PM after receptor-triggered activation of phospholipase C (PLC) (Bian et al, 2018; Saheki et al, 2016). This proposed role of E-Syts in DAG homeostasis has been further supported by the finding that E-Syt1 regulates insulin secretion in pancreatic islets by clearing DAG from the PM (Xie et al, 2019).…”

“…Interestingly, although no significant alterations in steady-state PM glycerolipids were detected in genome-edited cells lacking all E-Syts, a transient accumulation of DAG after PLC activation was observed, supporting their role in DAG transport (Saheki et al, 2016). This function was further reinforced from the analysis of pancreatic islets, where a decreased expression of E-Syt1 resulted in prolonged accumulation of DAG in the PM causing an increase in insulin secretion (Xie et al, 2019).…”

Lipid transporter TMEM24/C2CD2L is a Ca 2+ -regulated component of ER–plasma membrane contacts in mammalian neurons

“…However, the specific contribution of these proteins as ER-PM tethers in neurons remains unclear. E-Syt1, in particular, whose Ca 2+ -dependent recruitment to the PM shows nearly opposite dynamics relative to TMEM24 dissociation from this membrane when transfected in the same cell (46), is not expressed at high levels in brain (47) and analysis of brain singlecell genomics data reveals its preferential expression in nonneuronal cells (48).…”

Endoplasmic reticulum–plasma membrane contacts: Principals of phosphoinositide and calcium signaling

“…Dynamic events at ER-PM contacts control flux through the phosphoinositide cycle. Two recent studies (within the current period of the review) have described distinct roles for the extended synaptotagmins (E-Syts) and TMEM24 proteins at ER-PM contacts in the control of pulsatile insulin secretion [20,21]. Upon Ca 2+ -stimulated exocytosis, the Ca 2+ -activated E-Syts are proposed to transfer DG from the PM to the ER via their SMP (synaptotagmin-like mitochondrial lipid-binding protein domain) domains ( Figures 1A and 2A) [22].…”