Exocytosis in Islet β-Cells

Kasai, Hideaki; Hatakeyama, Hiroyasu; Ohno, Mitsuyo; Takahashi, Noriko

doi:10.1007/978-90-481-3271-3_14

Cited by 31 publications

(7 citation statements)

References 153 publications

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“…It should be noted that the first phase of insulin secretion in response to glucose is known to be crucially associated with membrane voltage changes, whereas the second phase is reported to be largely driven by Ca 2+ channels that are less dependent on membrane voltage34. This explains why CFRD patients lack the first phase of insulin secretion24, as the secretory granule mobilization associated with the first phase of insulin secretion is known to be dependent on voltage-gated Ca 2+ channels35. Interestingly, in contrast to the current belief that insulin insufficiency in CFRD is mainly due to destruction of the pancreatic islets6, our H&E examination revealed no significant difference in pancreatic islet morphology between CFTR wild-type and DF508 mice (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

et al. 2014

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The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in β-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca2+ oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse β-cells or RINm5F β-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 β-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in β-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy.

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Section: Discussionmentioning

confidence: 99%

Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

et al. 2014

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“…In contrast to polarized tubular epithelia constituting secretory glands, b cells are exposed to a relatively homogenous extracellular environment and do not form a lumen or display obvious membranal segregation (Kasai et al, 2010;Konstantinova and Lammert, 2004). In rodents, b cells are shaped as truncated pyramids that are clustered in rosette-like structures around blood vessels (illustrated in Figure 1A; Bonner -Weir, 1988;Weir and BonnerWeir, 1990).…”

Section: Introductionmentioning

confidence: 93%

The Edges of Pancreatic Islet β Cells Constitute Adhesive and Signaling Microdomains

et al. 2015

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Pancreatic islet β cells are organized in rosette-like structures around blood vessels and exhibit an artery-to-vein orientation, but they do not display the typical epithelial polarity. It is unclear whether these cells present a functional asymmetry related to their spatial organization. Here, we identify murine β cell edges, the sites at which adjacent cell faces meet at a sharp angle, as surface microdomains of cell-cell adhesion and signaling. The edges are marked by enrichment of F-actin and E-cadherin and are aligned between neighboring cells. The edge organization is E-cadherin contact dependent and correlates with insulin secretion capacity. Edges display elevated levels of glucose transporters and SNAP25 and extend numerous F-actin-rich filopodia. A similar β cell edge organization was observed in human islets. When stimulated, β cell edges exhibit high calcium levels. In view of the functional importance of intra-islet communication, the spatial architecture of their edges may prove fundamental for coordinating physiological insulin secretion.

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“…Amperometry studies show that the rapid increase in capacitance happens more quickly than LDCV exocytotic events in chromaffin cells (221,309,428,448,457), PC12 cells (448), ␤ cells (304,635), CHO cells (447), and mast cells (320) (FIGURE 1). The most likely reason for the dissociation between the capacitance and amperometric signals in these cells is the presence of small vesicle exocytosis.…”

Section: Small Vesicles In Nonneuronal Cellsmentioning

confidence: 98%

“…The second phase of insulin secretion is tonic and gives rise to glucose uptake into muscles and other tissues. In addition to Ca 2ϩ , cAMP is an important factor involved in insulin exocytosis (248,304,380,580). The two phases of insulin exocytosis are differentially regulated by PKA (237,308,634) and syntaxin (459,612), and may involve distinct molecular states (458,633).…”

Section: Endocrine Cellsmentioning

confidence: 99%

Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis

Kasai

Takahashi

Tokumaru

2012

Physiological Reviews

Self Cite

143

124

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The dynamics of exocytosis are diverse and have been optimized for the functions of synapses and a wide variety of cell types. For example, the kinetics of exocytosis varies by more than five orders of magnitude between ultrafast exocytosis in synaptic vesicles and slow exocytosis in large dense-core vesicles. However, in all cases, exocytosis is mediated by the same fundamental mechanism, i.e., the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. It is often assumed that vesicles need to be docked at the plasma membrane and SNARE proteins must be preassembled before exocytosis is triggered. However, this model cannot account for the dynamics of exocytosis recently reported in synapses and other cells. For example, vesicles undergo exocytosis without prestimulus docking during tonic exocytosis of synaptic vesicles in the active zone. In addition, epithelial and hematopoietic cells utilize cAMP and kinases to trigger slow exocytosis of nondocked vesicles. In this review, we summarize the manner in which the diversity of exocytosis reflects the initial configurations of SNARE assembly, including trans-SNARE, binary-SNARE, unitary-SNARE, and cis-SNARE configurations. The initial SNARE configurations depend on the particular SNARE subtype (syntaxin, SNAP25, or VAMP), priming proteins (Munc18, Munc13, CAPS, complexin, or snapin), triggering proteins (synaptotagmins, Doc2, and various protein kinases), and the submembraneous cytomatrix, and they are the key to determining the kinetics of subsequent exocytosis. These distinct initial configurations will help us clarify the common SNARE assembly processes underlying exocytosis and membrane trafficking in eukaryotic cells.

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Exocytosis in Islet β-Cells

Cited by 31 publications

References 153 publications

Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

The Edges of Pancreatic Islet β Cells Constitute Adhesive and Signaling Microdomains

Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis

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