Defective Secretion of Islet Hormones in Chromogranin-B Deficient Mice

Obermüller, Stefanie; Calegari, Federico; King, Angus; Lindqvist, Anders; Lundquist, Ingmar; Salehi, Albert; Francolini, Maura; Rosa, Patrizia; Rorsman, Patrik; Huttner, Wieland B.; Barg, Sebastian

doi:10.1371/journal.pone.0008936

Cited by 67 publications

(63 citation statements)

References 53 publications

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“…Under these conditions, it is possible that insulin plays a role as paracrine regulator of somatostatin release, since, at least in our hands, the two hormones were released at similar glucose concentrations. This is consistent with a previous study using human islets [10], but contrasts with other reports of enhanced delta cell sensitivity to glucose compared with beta cells, where glucose concentrations as low as 2 to 3 mmol/l initiated significant increases in somatostatin secretion from mouse islets [12,38,39]. Because of these reports, we routinely used a very low concentration of glucose (1 mmol/l) to assess basal, unstimulated levels of somatostatin secretion, but were consistently unable to detect any significant increases in somatostatin secretion from mouse islets at 5 mmol/l glucose, whereas we did observe (non-significant) increases in insulin and somatostatin release at 7 and 10 mmol/l glucose.…”

Section: Discussionsupporting

confidence: 91%

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

et al. 2012

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Aims/hypothesis Somatostatin from islet delta cells inhibits insulin and glucagon secretion, but knowledge of the regulation of pancreatic somatostatin release is limited. Some insulin secretagogues stimulate somatostatin secretion, and here we investigated whether delta cell secretory responses are indirectly regulated in a paracrine manner by insulin released from beta cells. Methods Hormone release from static incubations of primary mouse islets or somatostatin-secreting TGP52 cells was measured by RIA. mRNA expression was assessed by RT-PCR. Results Glucose and a range of other physiological and pharmacological agents stimulated insulin and somatostatin release, and insulin receptor mRNA was expressed in islets, MIN6 beta cells and TGP52 cells. However, exogenous insulin did not modulate basal or glucose-induced somatostatin secretion from islets, nor did pre-incubation with an antibody against the insulin receptor or with the insulin receptor tyrosine kinase inhibitor, HNMPA(AM) 3 . Glucose and tolbutamide stimulated somatostatin release from TGP52 cells, whereas a range of receptor-operating agents had no effect, the latter being consistent with a lack of corresponding receptor mRNA expression in these cells. Parasympathetic activation stimulated insulin, but inhibited somatostatin release from mouse islets in accordance with differences in muscarinic receptor mRNA expression in islets, MIN6 and TGP52 cells. The inhibitory effect on somatostatin secretion was reversed by pertussis toxin or the muscarinic receptor 2 antagonist, methoctramine. Conclusions/interpretations A number of insulin secretagogues have analogous effects on insulin and somatostatin release, but this similarity of response is not mediated by an indirect, paracrine action of insulin on delta cells.

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Section: Discussionsupporting

confidence: 91%

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

et al. 2012

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“…These mice developed a phenotype of hypertension ) and intolerance to glucose (Obermuller et al 2010). In contrast to the CgA-KO mouse, immuno-histochemistry and western blotting confirmed the absence of CgB and the overexpression of CgA (Fig.…”

Section: Catecholamine Exocytosis From Cgb-ko Chromaffin Cellsmentioning

confidence: 82%

Chromogranins A and B as Regulators of Vesicle Cargo and Exocytosis

et al. 2010

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Chromogranins (Cgs) are acidic proteins that have been implicated in several physiological processes such as vesicle sorting, the production of bioactive peptides and the accumulation of soluble species inside large dense core vesicles (LDCV). They constitute the main protein component in the vesicular matrix of LDCV. This latter characteristic of Cgs accounts for the ability of vesicles to concentrate catecholamines and Ca(2+). It is likely that Cgs are behind the delay in the neurotransmitter exit towards the extracellular milieu after vesicle fusion, due to their low affinity and high capacity to bind solutes present inside LDCV. The recent availability of mouse strains lacking Cgs, combined with the arrival of several techniques for the direct monitoring of exocytosis, have helped to expand our knowledge about the mechanisms used by granins to concentrate catecholamines and Ca(2+) in LDCV, and how they affect the kinetics of exocytosis. We will discuss the roles of Cgs A and B in maintaining the intravesicular environment of secretory vesicles and in exocytosis, bringing together the most recent findings from adrenal chromaffin cells.

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“…Further support came from complementary experiments, which showed that over-expression of chromogranin A in non-secretory cells resulted in the formation of secretory vesicles-like structures [38]. On the other hand, deletion of the chromogranin A gene did not affect the synthesis of proteins targeted to the secretory granules or their biogenesis [41] and, in other cell types, such as pancreatic β-cells, insulin vesicle biogenesis was completely independent from both chromogranin A and B [42, 43]. Moreover, chromogranin A ablation resulted in the compensatory expression of other granins.…”

Section: Regulated Exocytosismentioning

confidence: 99%

Multiple roles for the actin cytoskeleton during regulated exocytosis

Porat-Shliom

Milberg

Masedunskas

et al. 2012

Cell. Mol. Life Sci.

167

162

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Regulated exocytosis is the main mechanism utilized by specialized secretory cells to deliver molecules to the cell surface by virtue of membranous containers (i.e. secretory vesicles). The process involves a series of highly coordinated and sequential steps, which include the biogenesis of the vesicles, their delivery to the cell periphery, their fusion with the plasma membrane and the release of their content into the extracellular space. Each of these steps is regulated by the actin cytoskeleton. In this review, we summarize the current knowledge regarding the involvement of actin and its associated molecules during each of the exocytic steps in vertebrates, and suggest that the overall role of the actin cytoskeleton during regulated exocytosis is linked to the architecture and the physiology of the secretory cells under examination. Specifically, in neurons, neuroendocrine, endocrine, and hematopoietic cells, which contain small secretory vesicles that undergo rapid exocytosis (on the order of milliseconds), the actin cytoskeleton plays a role in pre-fusion events, where it acts primarily as a functional barrier and facilitates docking. In exocrine and other secretory cells, which contain large secretory vesicles that undergo slow exocytosis (seconds to minutes), the actin cytoskeleton plays a role in post-fusion events, where it regulates the dynamics of the fusion pore, facilitates the integration of the vesicles into the plasma membrane, provides structural support, and promotes the expulsion of large cargo molecules.

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Defective Secretion of Islet Hormones in Chromogranin-B Deficient Mice

Cited by 67 publications

References 53 publications

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin

Chromogranins A and B as Regulators of Vesicle Cargo and Exocytosis

Multiple roles for the actin cytoskeleton during regulated exocytosis

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