scholarly journals Melanophilin accelerates insulin granule fusion without predocking to the plasma membrane

2020 ◽  
Author(s):  
Ada Admin ◽  
Hao Wang ◽  
Kouichi Mizuno ◽  
Noriko Takahashi ◽  
Eri Kobayashi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Secretory Granule ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Granule Exocytosis ◽  
Synaptic Vesicle Exocytosis ◽  
Granule Membrane ◽  
Myosin Va ◽  
Vesicle Exocytosis ◽  
Glucose Stimulated Insulin Secretion

Direct observation of fluorescence-labeled secretory granule exocytosis in living pancreatic β cells has revealed heterogeneous prefusion behaviors: some granules dwell beneath the plasma membrane before fusion, while others fuse immediately once they are recruited to the plasma membrane. Although the former mode seems to follow sequential docking-priming-fusion steps as found in synaptic vesicle exocytosis, the latter mode, which is unique to secretory granule exocytosis, has not been explored well. Here, we show that melanophilin, one of the effectors of the monomeric GTPase Rab27 on the granule membrane, is involved in such an accelerated mode of exocytosis. Both melanophilin-mutated <i>leaden</i> mouse and melanophilin-downregulated human pancreatic β cells exhibit impaired glucose-stimulated insulin secretion, with a specific reduction in fusion events that bypass stable docking to the plasma membrane. Upon stimulus-induced [Ca<sup>2+</sup>]<sub>i</sub> rise, melanophilin mediates this type of fusion by dissociating granules from myosin-Va and actin in the actin cortex and by associating them with a fusion-competent, open form of syntaxin-4 on the plasma membrane. These findings provide the hitherto unknown mechanism to support sustainable exocytosis by which granules are recruited from the cell interior and fuse promptly without stable predocking to the plasma membrane.

scholarly journals Melanophilin accelerates insulin granule fusion without predocking to the plasma membrane

2020 ◽  
Author(s):  
Ada Admin ◽  
Hao Wang ◽  
Kouichi Mizuno ◽  
Noriko Takahashi ◽  
Eri Kobayashi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Secretory Granule ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Granule Exocytosis ◽  
Synaptic Vesicle Exocytosis ◽  
Granule Membrane ◽  
Myosin Va ◽  
Vesicle Exocytosis ◽  
Glucose Stimulated Insulin Secretion

Direct observation of fluorescence-labeled secretory granule exocytosis in living pancreatic β cells has revealed heterogeneous prefusion behaviors: some granules dwell beneath the plasma membrane before fusion, while others fuse immediately once they are recruited to the plasma membrane. Although the former mode seems to follow sequential docking-priming-fusion steps as found in synaptic vesicle exocytosis, the latter mode, which is unique to secretory granule exocytosis, has not been explored well. Here, we show that melanophilin, one of the effectors of the monomeric GTPase Rab27 on the granule membrane, is involved in such an accelerated mode of exocytosis. Both melanophilin-mutated <i>leaden</i> mouse and melanophilin-downregulated human pancreatic β cells exhibit impaired glucose-stimulated insulin secretion, with a specific reduction in fusion events that bypass stable docking to the plasma membrane. Upon stimulus-induced [Ca<sup>2+</sup>]<sub>i</sub> rise, melanophilin mediates this type of fusion by dissociating granules from myosin-Va and actin in the actin cortex and by associating them with a fusion-competent, open form of syntaxin-4 on the plasma membrane. These findings provide the hitherto unknown mechanism to support sustainable exocytosis by which granules are recruited from the cell interior and fuse promptly without stable predocking to the plasma membrane.

scholarly journals Melanophilin accelerates insulin granule fusion without predocking to the plasma membrane

2020 ◽  
Author(s):  
Ada Admin ◽  
Hao Wang ◽  
Kouichi Mizuno ◽  
Noriko Takahashi ◽  
Eri Kobayashi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Secretory Granule ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Granule Exocytosis ◽  
Synaptic Vesicle Exocytosis ◽  
Granule Membrane ◽  
Myosin Va ◽  
Vesicle Exocytosis ◽  
Glucose Stimulated Insulin Secretion

Direct observation of fluorescence-labeled secretory granule exocytosis in living pancreatic β cells has revealed heterogeneous prefusion behaviors: some granules dwell beneath the plasma membrane before fusion, while others fuse immediately once they are recruited to the plasma membrane. Although the former mode seems to follow sequential docking-priming-fusion steps as found in synaptic vesicle exocytosis, the latter mode, which is unique to secretory granule exocytosis, has not been explored well. Here, we show that melanophilin, one of the effectors of the monomeric GTPase Rab27 on the granule membrane, is involved in such an accelerated mode of exocytosis. Both melanophilin-mutated <i>leaden</i> mouse and melanophilin-downregulated human pancreatic β cells exhibit impaired glucose-stimulated insulin secretion, with a specific reduction in fusion events that bypass stable docking to the plasma membrane. Upon stimulus-induced [Ca<sup>2+</sup>]<sub>i</sub> rise, melanophilin mediates this type of fusion by dissociating granules from myosin-Va and actin in the actin cortex and by associating them with a fusion-competent, open form of syntaxin-4 on the plasma membrane. These findings provide the hitherto unknown mechanism to support sustainable exocytosis by which granules are recruited from the cell interior and fuse promptly without stable predocking to the plasma membrane.

Secretory Granule Exocytosis

2003 ◽  
Vol 83 (2) ◽  
pp. 581-632 ◽  
Author(s):  
Robert D. Burgoyne ◽  
Alan Morgan
Keyword(s):  
Secretory Granule ◽  
Secretory Granules ◽  
Physiological Role ◽  
Cell Types ◽  
Control Mechanisms ◽  
Granule Exocytosis ◽  
Synaptic Vesicle Exocytosis ◽  
Wide Range ◽  
Vesicle Exocytosis ◽  
Protein Components

Regulated exocytosis of secretory granules or dense-core granules has been examined in many well-characterized cell types including neurons, neuroendocrine, endocrine, exocrine, and hemopoietic cells and also in other less well-studied cell types. Secretory granule exocytosis occurs through mechanisms with many aspects in common with synaptic vesicle exocytosis and most likely uses the same basic protein components. Despite the widespread expression and conservation of a core exocytotic machinery, many variations occur in the control of secretory granule exocytosis that are related to the specialized physiological role of particular cell types. In this review we describe the wide range of cell types in which regulated secretory granule exocytosis occurs and assess the evidence for the expression of the conserved fusion machinery in these cells. The signals that trigger and regulate exocytosis are reviewed. Aspects of the control of exocytosis that are specific for secretory granules compared with synaptic vesicles or for particular cell types are described and compared to define the range of accessory control mechanisms that exert their effects on the core exocytotic machinery.

scholarly journals Redox Signaling is Essential for Insulin Secretion

2021 ◽  
Author(s):  
Petr Ježek ◽  
Blanka Holendová ◽  
Martin Jabůrek ◽  
Jan Tauber ◽  
Andrea Dlasková ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Secretion ◽  
Redox Signaling ◽  
H2o2 Production ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Nadph Oxidase 4 ◽  
Elevated Glucose ◽  
Branched Chain ◽  
Glucose Stimulated Insulin Secretion

In this review, we place redox signaling in pancreatic β-cells to the context with signaling pathways leading to insulin secretion, acting for example upon the action of incretins (GLP-1, GIP) and the metabotropic receptor GPR40. Besides a brief description of ion channel participation in depolarization/repolarization of the plasma membrane, we emphasize a prominent role of the elevated glucose level in pancreatic β-cells during glucose-stimulated insulin secretion (GSIS). We focus on our recent findings, which revealed that for GSIS, not only elevated ATP synthesis is required, but also fundamental redox signaling originating from the NADPH oxidase 4- (NOX4-) mediated H2O2 production. We hypothesized that the closing of the ATP-sensitive K+ channel (KATP) is only possible when both ATP plus H2O2 are elevated in INS-1E cells. KATP alone or with synergic channels provides an element of logical sum, integrating both metabolic plus redox homeostasis. This is also valid for other secretagogues, such as branched chain ketoacids (BCKAs); and partly for fatty acids (FAs). Branched chain aminoacids, leucine, valine and isoleucine, after being converted to BCKAs are metabolized by a series of reactions resembling β-oxidation of FAs. This increases superoxide formation in mitochondria, including its portion elevated due to the function of electron transfer flavoprotein ubiquinone oxidoreductase (ETF:QOR). After superoxide conversion to H2O2 the oxidation of BCKAs provides the mitochondrial redox signaling extending up to the plasma membrane to induce its depolarization together with the elevated ATP. In contrast, experimental FA-stimulated insulin secretion in the presence of non-stimulating glucose concentrations is predominantly mediated by GPR40, for which intramitochondrial redox signaling activates phospholipase iPLA2γ, cleaving free FAs from mitochondrial membranes, which diffuse to the plasma membrane and largely amplify the GPR40 response. These events are concomitant to the insulin release due to the metabolic component. Hypothetically, redox signaling may proceed by simple H2O2 diffusion or via an SH-relay enabled by peroxiredoxins to target proteins. However, these aspects have yet to be elucidated.

scholarly journals Granular detail of β cell structures for insulin secretion

2021 ◽  
Vol 220 (2) ◽  
Author(s):  
Jonathan S. Bogan
Keyword(s):  
Insulin Secretion ◽  
Secretory Granule ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulation ◽  
Granule Exocytosis ◽  
Cell Biol ◽  
Cell Structures ◽  
Insulin Secretory Granule

Pancreatic β cells secrete insulin in response to increased glucose concentrations. Müller et al. (2021. J. Cell Biol. https://doi.org/10.1083/jcb.202010039) use 3D FIB-SEM to study the architecture of these cells and to elucidate how glucose stimulation remodels microtubules to control insulin secretory granule exocytosis.

scholarly journals Brain-selective Kinase 2 (BRSK2) Phosphorylation on PCTAIRE1 Negatively Regulates Glucose-stimulated Insulin Secretion in Pancreatic β-Cells

2012 ◽  
Vol 287 (36) ◽  
pp. 30368-30375 ◽  
Author(s):  
Xin-Ya Chen ◽  
Xiu-Ting Gu ◽  
Hexige Saiyin ◽  
Bo Wan ◽  
Yu-Jing Zhang ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

scholarly journals A Novel Tetanus Neurotoxin-insensitive Vesicle-associated Membrane Protein in SNARE Complexes of the Apical Plasma Membrane of Epithelial Cells

1998 ◽  
Vol 9 (6) ◽  
pp. 1437-1448 ◽  
Author(s):  
Thierry Galli ◽  
Ahmed Zahraoui ◽  
Vadakkanchery V. Vaidyanathan ◽  
Graça Raposo ◽  
Jian Min Tian ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Epithelial Cells ◽  
Membrane Protein ◽  
Apical Plasma Membrane ◽  
Domain Specific ◽  
Tetanus Neurotoxin ◽  
Synaptic Vesicle Exocytosis ◽  
Clostridial Neurotoxins ◽  
Vesicle Exocytosis ◽  
Syntaxin 3

The importance of soluble N-ethyl maleimide (NEM)-sensitive fusion protein (NSF) attachment protein (SNAP) receptors (SNAREs) in synaptic vesicle exocytosis is well established because it has been demonstrated that clostridial neurotoxins (NTs) proteolyze the vesicle SNAREs (v-SNAREs) vesicle-associated membrane protein (VAMP)/brevins and their partners, the target SNAREs (t-SNAREs) syntaxin 1 and SNAP25. Yet, several exocytotic events, including apical exocytosis in epithelial cells, are insensitive to numerous clostridial NTs, suggesting the presence of SNARE-independent mechanisms of exocytosis. In this study we found that syntaxin 3, SNAP23, and a newly identified VAMP/brevin, tetanus neurotoxin (TeNT)-insensitive VAMP (TI-VAMP), are insensitive to clostridial NTs. In epithelial cells, TI-VAMP–containing vesicles were concentrated in the apical domain, and the protein was detected at the apical plasma membrane by immunogold labeling on ultrathin cryosections. Syntaxin 3 and SNAP23 were codistributed at the apical plasma membrane where they formed NEM-dependent SNARE complexes with TI-VAMP and cellubrevin. We suggest that TI-VAMP, SNAP23, and syntaxin 3 can participate in exocytotic processes at the apical plasma membrane of epithelial cells and, more generally, domain-specific exocytosis in clostridial NT-resistant pathways.

scholarly journals Peroxisome Proliferator-Activated Receptor α (PPARα) Potentiates, whereas PPARγ Attenuates, Glucose-Stimulated Insulin Secretion in Pancreatic β-Cells

Endocrinology ◽  
2005 ◽  
Vol 146 (8) ◽  
pp. 3266-3276 ◽  
Author(s):  
Kim Ravnskjaer ◽  
Michael Boergesen ◽  
Blanca Rubi ◽  
Jan K. Larsen ◽  
Tina Nielsen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mitochondrial Membrane ◽  
Uncoupling Protein ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Stimulated Insulin Secretion

Abstract Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic β-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of β-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARα and retinoid X receptor α (RXRα) in INS-1E β-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARα target genes and enhances FA uptake and β-oxidation. In contrast, ectopic expression of PPARγ/RXRα increases FA uptake and deposition as triacylglycerides. Although the expression of PPARα/RXRα leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARγ/RXRα attenuates GSIS, the expression of PPARα/RXRα potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes α and γ on lipid partitioning and insulin secretion when systematically compared in a β-cell context.

scholarly journals L-Arginine prevents cereblon-mediated ubiquitination of glucokinase and stimulates glucose-6-phosphate production in pancreatic β-cells

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Jaeyong Cho ◽  
Yukio Horikawa ◽  
Mayumi Enya ◽  
Jun Takeda ◽  
Yoichi Imai ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Direct Stimulation ◽  
Glucose Ratio ◽  
Glucose Stimulated Insulin Secretion

Abstract We sought to determine a mechanism by which L-arginine increases glucose-stimulated insulin secretion (GSIS) in β-cells by finding a protein with affinity to L-arginine using arginine-immobilized magnetic nanobeads technology. Glucokinase (GCK), the key regulator of GSIS and a disease-causing gene of maturity-onset diabetes of the young type 2 (MODY2), was found to bind L-arginine. L-Arginine stimulated production of glucose-6-phosphate (G6P) and induced insulin secretion. We analyzed glucokinase mutants and identified three glutamate residues that mediate binding to L-arginine. One MODY2 patient with GCKE442* demonstrated lower C-peptide-to-glucose ratio after arginine administration. In β-cell line, GCKE442* reduced L-arginine-induced insulin secretion compared with GCKWT. In addition, we elucidated that the binding of arginine protects glucokinase from degradation by E3 ubiquitin ligase cereblon mediated ubiquitination. We conclude that L-arginine induces insulin secretion by increasing G6P production by glucokinase through direct stimulation and by prevention of degradation.

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