Cell Swelling-induced Insulin Secretion from INS-1E Cells is Inhibited by Extracellular Ca&lt;sup&gt;2+&lt;/sup&gt; and is Tetanus Toxin Resistant

Orečná, Martina; Hafko, Roman; Toporcerová, Veronika; Štrbák, Vladimír; Bačová, Zuzana

doi:10.1159/000320543

Cited by 7 publications

(7 citation statements)

References 33 publications

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“…Recently, it has been reported that Nifedipine prevented induced apoptosis in endothelial cells and smooth muscle cells [40,41]. The l -type Ca 2+ channel has been reportedly expressed in INS-1 β-cells [42,43], and β-cells were also thought to be sensitive to calcium channel blockers [44], and Jeffrey et al . demonstrated that blocking Ca 2+ influx with nifedipine could abolish the palmitate-induced ER stress [45].…”

Section: Discussionmentioning

confidence: 99%

Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis

Wang

Gao

et al. 2011

IJMS

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Sustained high concentration of glucose has been verified toxic to β-cells. Glucose augments Ca2+-stimulated insulin release in pancreatic β-cells, but chronic high concentration of glucose could induce a sustained level of Ca2+ in β-cells, which leads to cell apoptosis. However, the mechanism of high glucose-induced β-cell apoptosis remains unclear. In this study, we use a calcium channel blocker, nifedipine, to investigate whether the inhibition of intracellular Ca2+ concentration could protect β-cells from chronic high glucose-induced apoptosis. It was found that in a concentration of 33.3 mM, chronic stimulation of glucose could induce INS-1 β-cells apoptosis at least through the endoplasmic reticulum stress pathway and 10 μM nifedipine inhibited Ca2+ release to protect β-cells from high glucose-induced endoplasmic reticulum stress and apoptosis. These results indicated that inhibition of Ca2+ over-accumulation might provide benefit to attenuate islet β-cell decompensation in a high glucose environment.

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Section: Discussionmentioning

confidence: 99%

Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis

Wang

Gao

et al. 2011

IJMS

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“…These results are indeed expected when considering the proposal that Ca 2+ -independent pathways contribute minimally to GSIS 78 . However, they also suggest that the modulatory effect that KCC2 inhibition has on insulin secretion does not involve potential secretory mechanisms, which are not dependent on Ca 2+ entry such as hypotonicity-induced cell swelling 79 or increased cAMP 80 . Although it has been reported that β-cell membrane potential does not change in response to 1.1 mM, 3.3 mM or 5.5 mM glucose 81 , a detailed analysis as that performed recently 23 will be needed to elucidate the mechanisms whereby KCC2 inhibition promotes Ca 2+ entry.…”

Section: Discussionmentioning

confidence: 99%

The neuronal K+Cl− co-transporter 2 (Slc12a5) modulates insulin secretion

Kursan

McMillen

Beesetty

et al. 2017

Sci Rep

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Intracellular chloride concentration ([Cl−]i) in pancreatic β-cells is kept above electrochemical equilibrium due to the predominant functional presence of Cl− loaders such as the Na+K+2Cl− co-transporter 1 (Slc12a2) over Cl−extruders of unidentified nature. Using molecular cloning, RT-PCR, Western blotting, immunolocalization and in vitro functional assays, we establish that the “neuron-specific” K+Cl− co-transporter 2 (KCC2, Slc12a5) is expressed in several endocrine cells of the pancreatic islet, including glucagon secreting α-cells, but particularly in insulin-secreting β-cells, where we provide evidence for its role in the insulin secretory response. Three KCC2 splice variants were identified: the formerly described KCC2a and KCC2b along with a novel one lacking exon 25 (KCC2a-S25). This new variant is undetectable in brain or spinal cord, the only and most abundant known sources of KCC2. Inhibition of KCC2 activity in clonal MIN6 β-cells increases basal and glucose-stimulated insulin secretion and Ca2+ uptake in the presence of glibenclamide, an inhibitor of the ATP-dependent potassium (KATP)-channels, thus suggesting a possible mechanism underlying KCC2-dependent insulin release. We propose that the long-time considered “neuron-specific” KCC2 co-transporter is expressed in pancreatic islet β-cells where it modulates Ca2+-dependent insulin secretion.

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“…Inhibition of L-type and/or P/Q-type calcium channels also enabled distinct response to hypotonic medium of INS-1E cells in Ca 2+ containing medium [86]. At these conditions tetanus toxin inhibited hypotonicity -induced insulin secretion from INS-1 cells but not from INS-1E cells [86]. Interesting enough, Straub et al [50] found two different exocytotic mechanisms operating in hyposmotic shock in GH4Cl cells in the presence and absence of Ca 2+ in the medium.…”

Section: Ins-1 and Ins-1e Cellsmentioning

confidence: 95%

“…They found that desorption of cholesterol leads to the disturbance of a basic exocytotic mechanism partly due to migration of SNAP-25, and concluded that insulin secretion is highly sensitive to changes in plasma membrane cholesterol. In our recent experiments comparison of two insulin secreting tumor cell lines revealed surprising differences: while INS-1 line responded to both glucose and hyposmotic stimulation, INS-1E was unable to respond to osmotic stimulus while response to glucose was regular [56,86]. Cellular content of cholesterol of INS-1E was much higher than that of INS-1 [87].…”

Section: N-ethylmaleimide-sensitive-factor (Nsf) and Soluble Nsf-attamentioning

confidence: 99%

“…We compared response of freshly isolated rat pancreatic islets with these tumor lines [56]; in Ca -depleted medium showed distinct secretory response of INS-1E cells to hypotonicity while that of INS-1 cells was partially inhibited [56]. Inhibition of L-type and/or P/Q-type calcium channels also enabled distinct response to hypotonic medium of INS-1E cells in Ca 2+ containing medium [86]. At these conditions tetanus toxin inhibited hypotonicity -induced insulin secretion from INS-1 cells but not from INS-1E cells [86].…”

Section: Ins-1 and Ins-1e Cellsmentioning

confidence: 99%

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Cell Swelling-induced Peptide Hormone Secretion

Štrbák

2011

Cell Physiol Biochem

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Cell swelling induces peptide exocytosis using unique signaling pathway. Hyposmotic-induced secretion in normal cells is not mediated by specific receptors, is independent from extra and intracellular Ca²⁺, sodium and potassium channels activity, prostaglandins, leukotriens, does not involve cytoskeleton, cAMP generation, phospholipase A₂, G proteins, protein kinase C. It is promoted by swelling of the secretory vesicles. Resistance to endogenous inhibitors is frequent attribute of this type of secretion. Swelling-induced secretion involves also secretory vesicles not involved in conventional stimulation. Hyposmosis-induced insulin secretion is more sensitive to high cellular cholesterol than conventional one suggesting substantial difference between mechanisms. Participation of sequential exocytosis as dominating mechanism in swelling-induced exocytosis is hypothesized. Signaling and response in tumor cells often differs from native cells and varies markedly between cell lines. Pathogenetic implications: cell swelling could be involved in alcohol induced hypoglycemia in diabetic patients and release of peptides from pituitary and neurons. Swelling-induced products could be mediators of ischemic preconditioning involved also in protection of diabetic heart. Swelling-induced exocytosis is an ancient mechanism generally present in cells; in cells engaged in water and salt regulation is covered by specific response mediated by specific signaling. Disturbance of specific response leads to swelling-induced - inappropriate secretion of antidiuretic hormone - SIADH.

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Cell Swelling-induced Insulin Secretion from INS-1E Cells is Inhibited by Extracellular Ca<sup>2+</sup> and is Tetanus Toxin Resistant

Cited by 7 publications

References 33 publications

Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis

Nifedipine Protects INS-1 β-Cell from High Glucose-Induced ER Stress and Apoptosis

The neuronal K+Cl− co-transporter 2 (Slc12a5) modulates insulin secretion

Cell Swelling-induced Peptide Hormone Secretion

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