scholarly journals Biophysical and pharmacological properties of the voltage-gated potassium current of human pancreatic β-cells

2005 ◽  
Vol 567 (1) ◽  
pp. 159-175 ◽  
Author(s):  
James Herrington ◽  
Manuel Sanchez ◽  
Denize Wunderler ◽  
Lizhen Yan ◽  
Randal M. Bugianesi ◽  
...  
Keyword(s):  
Potassium Current ◽  
Pharmacological Properties ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Voltage Gated

scholarly journals Regulation of voltage-gated K+channels by glucose metabolism in pancreatic β-cells

FEBS Letters ◽  
2009 ◽  
Vol 583 (13) ◽  
pp. 2225-2230 ◽  
Author(s):  
Masashi Yoshida ◽  
Katsuya Dezaki ◽  
Shiho Yamato ◽  
Atsushi Aoki ◽  
Hitoshi Sugawara ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Voltage Gated

scholarly journals Reduction in Voltage-Gated K+ Currents in Primary Cultured Rat Pancreatic β-Cells by Linoleic Acids

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 674-682 ◽  
Author(s):  
Dan Dan Feng ◽  
Ziqiang Luo ◽  
Sang-gun Roh ◽  
Maria Hernandez ◽  
Neveen Tawadros ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Linoleic Acid ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Voltage Gated ◽  
K Current ◽  
K Currents ◽  
Kinase A

Free fatty acids (FFAs), in addition to glucose, have been shown to stimulate insulin release through the G protein-coupled receptor (GPCR)40 receptor in pancreatic β-cells. Intracellular free calcium concentration ([Ca2+]i) in β-cells is elevated by FFAs, although the mechanism underlying the [Ca2+]i increase is still unknown. In this study, we investigated the action of linoleic acid on voltage-gated K+ currents. Nystatin-perforated recordings were performed on identified rat β-cells. In the presence of nifedipine, tetrodotoxin, and tolbutamide, voltage-gated K+ currents were observed. The transient current represents less than 5%, whereas the delayed rectifier current comprises more than 95%, of the total K+ currents. A long-chain unsaturated FFA, linoleic acid (10 μm), reversibly decreased the amplitude of K+ currents (to less than 10%). This reduction was abolished by the cAMP/protein kinase A system inhibitors H89 (1 μm) and Rp-cAMP (10 μm) but was not affected by protein kinase C inhibitor. In addition, forskolin and 8′-bromo-cAMP induced a similar reduction in the K+ current as that evoked by linoleic acid. Insulin secretion and cAMP accumulation in β-cells were also increased by linoleic acid. Methyl linoleate, which has a similar structure to linoleic acid but no binding affinity to GPR40, did not change K+ currents. Treatment of cultured cells with GPR40-specific small interfering RNA significantly reduced the decrease in K+ current induced by linoleic acid, whereas the cAMP-induced reduction of K+ current was not affected. We conclude that linoleic acid reduces the voltage-gated K+ current in rat β-cells through GPR40 and the cAMP-protein kinase A system, leading to an increase in [Ca2+]i and insulin secretion.

Inhibition of voltage-gated K+ channels mediates docosahexaenoic acid-stimulated insulin secretion in rat pancreatic β-cells

2020 ◽  
Vol 11 (10) ◽  
pp. 8893-8904
Author(s):  
Tao Bai ◽  
Huanhuan Yang ◽  
Hui Wang ◽  
Linping Zhi ◽  
Tao Liu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Docosahexaenoic Acid ◽  
Signaling Pathway ◽  
Vital Role ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Voltage Gated ◽  
Kv Channels

Kv channels play a vital role in DHA-augmented insulin secretion through GPR40/AC/cAMP/PLC signaling pathway in rat pancreatic β-cells.

scholarly journals Somatostatin Inhibits Oxidative Respiration in Pancreatic β-Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1527-1535 ◽  
Author(s):  
Mathew Daunt ◽  
Oliver Dale ◽  
Paul A. Smith
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Somatostatin Receptor ◽  
Katp Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
K Channels ◽  
Min6 Cells ◽  
Voltage Gated ◽  
Mouse Islets

Somatostatin potently inhibits insulin secretion from pancreatic β-cells. It does so via activation of ATP-sensitive K+-channels (KATP) and G protein-regulated inwardly rectifying K+-channels, which act to decrease voltage-gated Ca2+-influx, a process central to exocytosis. Because KATP channels, and indeed insulin secretion, is controlled by glucose oxidation, we investigated whether somatostatin inhibits insulin secretion by direct effects on glucose metabolism. Oxidative metabolism in β-cells was monitored by measuring changes in the O2 consumption (ΔO2) of isolated mouse islets and MIN6 cells, a murine-derived β-cell line. In both models, glucose-stimulated ΔO2, an effect closely associated with inhibition of KATP channel activity and induction of electrical activity (r > 0.98). At 100 nm, somatostatin abolished glucose-stimulated ΔO2 in mouse islets (n = 5, P < 0.05) and inhibited it by 80 ± 28% (n = 17, P < 0.01) in MIN6 cells. Removal of extracellular Ca2+, 5 mm Co2+, or 20 μm nifedipine, conditions that inhibit voltage-gated Ca2+ influx, did not mimic but either blocked or reduced the effect of the peptide on ΔO2. The nutrient secretagogues, methylpyruvate (10 mm) and α-ketoisocaproate (20 mm), also stimulated ΔO2, but this was unaffected by somatostatin. Somatostatin also reversed glucose-induced hyperpolarization of the mitochondrial membrane potential monitored using rhodamine-123. Application of somatostatin receptor selective agonists demonstrated that the peptide worked through activation of the type 5 somatostatin receptor. In conclusion, somatostatin inhibits glucose metabolism in murine β-cells by an unidentified Ca2+-dependent mechanism. This represents a new signaling pathway by which somatostatin can inhibit cellular functions regulated by glucose metabolism.

scholarly journals Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic β-Cells

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 5136-5145 ◽  
Author(s):  
Fuzhen Xia ◽  
Li Xie ◽  
Anton Mihic ◽  
Xiaodong Gao ◽  
Yi Chen ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pancreatic Islets ◽  
Cholesterol Biosynthesis ◽  
Squalene Epoxidase ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Min6 Cells ◽  
Voltage Gated ◽  
Endogenous Cholesterol

Insulin secretion from pancreatic β-cells is mediated by the opening of voltage-gated Ca2+ channels (CaV) and exocytosis of insulin dense core vesicles facilitated by the secretory soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein machinery. We previously observed that β-cell exocytosis is sensitive to the acute removal of membrane cholesterol. However, less is known about the chronic changes in endogenous cholesterol and its biosynthesis in regulating β-cell stimulus-secretion coupling. We examined the effects of inhibiting endogenous β-cell cholesterol biosynthesis by using the squalene epoxidase inhibitor, NB598. The expression of squalene epoxidase in primary and clonal β-cells was confirmed by RT-PCR. Cholesterol reduction of 36–52% was observed in MIN6 cells, mouse and human pancreatic islets after a 48-h incubation with 10 μm NB598. A similar reduction in cholesterol was observed in the subcellular compartments of MIN6 cells. We found NB598 significantly inhibited both basal and glucose-stimulated insulin secretion from mouse pancreatic islets. CaV channels were markedly inhibited by NB598. Rapid photolytic release of intracellular caged Ca2+ and simultaneous measurements of the changes in membrane capacitance revealed that NB598 also inhibited exocytosis independently from CaV channels. These effects were reversed by cholesterol repletion. Our results indicate that endogenous cholesterol in pancreatic β-cells plays a critical role in regulating insulin secretion. Moreover, chronic inhibition of cholesterol biosynthesis regulates the functional activity of CaV channels and insulin secretory granule mobilization and membrane fusion. Dysregulation of cellular cholesterol may cause impairment of β-cell function, a possible pathogenesis leading to the development of type 2 diabetes.

scholarly journals PIP2 in pancreatic β-cells regulates voltage-gated calcium channels by a voltage-independent pathway

2016 ◽  
Vol 311 (4) ◽  
pp. C630-C640 ◽  
Author(s):  
Lizbeth de la Cruz ◽  
Erika I. Puente ◽  
Arturo Reyes-Vaca ◽  
Isabel Arenas ◽  
Julieta Garduño ◽  
...  
Keyword(s):  
Ion Channels ◽  
Temporal Association ◽  
Membrane Phospholipids ◽  
High Concentration ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Patch Clamp Technique ◽  
Voltage Gated ◽  
Channel Inhibition ◽  
Insulin Secreting Cells

Phosphatidylinositol-4,5-bisphosphate (PIP2) is a membrane phosphoinositide that regulates the activity of many ion channels. Influx of calcium primarily through voltage-gated calcium (CaV) channels promotes insulin secretion in pancreatic β-cells. However, whether CaV channels are regulated by PIP2, as is the case for some non-insulin-secreting cells, is unknown. The purpose of this study was to investigate whether CaV channels are regulated by PIP2 depletion in pancreatic β-cells through activation of a muscarinic pathway induced by oxotremorine methiodide (Oxo-M). CaV channel currents were recorded by the patch-clamp technique. The CaV current amplitude was reduced by activation of the muscarinic receptor 1 (M1R) in the absence of kinetic changes. The Oxo-M-induced inhibition exhibited the hallmarks of voltage-independent regulation and did not involve PKC activation. A small fraction of the Oxo-M-induced CaV inhibition was diminished by a high concentration of Ca2+ chelator, whereas ≥50% of this inhibition was prevented by diC8-PIP2 dialysis. Localization of PIP2 in the plasma membrane was examined by transfecting INS-1 cells with PH-PLCδ1, which revealed a close temporal association between PIP2 hydrolysis and CaV channel inhibition. Furthermore, the depletion of PIP2 by a voltage-sensitive phosphatase reduced CaV currents in a way similar to that observed following M1R activation. These results indicate that activation of the M1R pathway inhibits the CaV channel via PIP2 depletion by a Ca2+-dependent mechanism in pancreatic β- and INS-1 cells and thereby support the hypothesis that membrane phospholipids regulate ion channel activity by interacting with ion channels.

scholarly journals Loss of the voltage-gated proton channel Hv1 decreases insulin secretion and leads to hyperglycemia and glucose intolerance in mice

2020 ◽  
Vol 295 (11) ◽  
pp. 3601-3613 ◽  
Author(s):  
Huimin Pang ◽  
Xudong Wang ◽  
Shiqun Zhao ◽  
Wang Xi ◽  
Jili Lv ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Intolerance ◽  
Glucose Homeostasis ◽  
Membrane Depolarization ◽  
Proton Channel ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Voltage Gated ◽  
Deficient Mice

Insulin secretion by pancreatic islet β-cells is regulated by glucose levels and is accompanied by proton generation. The voltage-gated proton channel Hv1 is present in pancreatic β-cells and extremely selective for protons. However, whether Hv1 is involved in insulin secretion is unclear. Here we demonstrate that Hv1 promotes insulin secretion of pancreatic β-cells and glucose homeostasis. Hv1-deficient mice displayed hyperglycemia and glucose intolerance because of reduced insulin secretion but retained normal peripheral insulin sensitivity. Moreover, Hv1 loss contributed much more to severe glucose intolerance as the mice got older. Islets of Hv1-deficient and heterozygous mice were markedly deficient in glucose- and K+-induced insulin secretion. In perifusion assays, Hv1 deletion dramatically reduced the first and second phase of glucose-stimulated insulin secretion. Islet insulin and proinsulin content was reduced, and histological analysis of pancreas slices revealed an accompanying modest reduction of β-cell mass in Hv1 knockout mice. EM observations also indicated a reduction in insulin granule size, but not granule number or granule docking, in Hv1-deficient mice. Mechanistically, Hv1 loss limited the capacity for glucose-induced membrane depolarization, accompanied by a reduced ability of glucose to raise Ca2+ levels in islets, as evidenced by decreased durations of individual calcium oscillations. Moreover, Hv1 expression was significantly reduced in pancreatic β-cells from streptozotocin-induced diabetic mice, indicating that Hv1 deficiency is associated with β-cell dysfunction and diabetes. We conclude that Hv1 regulates insulin secretion and glucose homeostasis through a mechanism that depends on intracellular Ca2+ levels and membrane depolarization.

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