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

Feng, Dan; Luo, Ziqiang; Roh, Sanggun; Hernandez, Maria; Tawadros, Neveen; Keating, Damien J.; Chen, Chen

doi:10.1210/en.2005-0225

Cited by 118 publications

(85 citation statements)

References 38 publications

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“…Carbachol also induces accumulation of inositol trisphosphates (18) and diacylglycerol (14) in islets by a BELinsensitive mechanism that probably involves coupling of the muscarinic receptor with a G-protein that activates a phospholipase C. Accumulation of diacylglycerol in phospholipid bilayers facilitates PLA 2 activation (63, 64) and phospholipids hydrolysis to yield free fatty acids, such as arachidonic acid or linoleic acid (50,51), near Kv2.1 channels might affect channel activity. We observe that carbachol shortens the depolarization-induced time-to-peak Kv2.1 current and accelerates current inactivation in INS-1 cells and primary mouse ␤-cells; the latter effect is prevented by the iPLA 2 ␤ inhibitor BEL or in cells from genetically modified mice that do not express iPLA 2 ␤.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

Jacobson

Weber

Bao

et al. 2007

Journal of Biological Chemistry

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Glucose stimulates both insulin secretion and hydrolysis of arachidonic acid (AA) esterified in membrane phospholipids of pancreatic islet ␤-cells, and these processes are amplified by muscarinic agonists. Here we demonstrate that nonesterified AA regulates the biophysical activity of the pancreatic islet ␤-cell-delayed rectifier channel, Kv2.1. Recordings of Kv2.1 currents from INS-1 insulinoma cells incubated with AA (5 M) and subjected to graded degrees of depolarization exhibit a significantly shorter time-to-peak current interval than do control cells. AA causes a rapid decay and reduced peak conductance of delayed rectifier currents from INS-1 cells and from primary ␤-cells isolated from mouse, rat, and human pancreatic islets. Stimulating mouse islets with AA results in a significant increase in the frequency of glucoseinduced [Ca 2؉ ] oscillations, which is an expected effect of Kv2.1 channel blockade. Stimulation with concentrations of glucose and carbachol that accelerate hydrolysis of endogenous AA from islet phosphoplipids also results in accelerated Kv2.1 inactivation and a shorter time-to-peak current interval. Group VIA phospholipase A 2 (iPLA 2 ␤) hydrolyzes ␤-cell membrane phospholipids to release nonesterified fatty acids, including AA, and inhibiting iPLA 2 ␤ prevents the muscarinic agonist-induced accelerated Kv2.1 inactivation. Furthermore, glucose and carbachol do not significantly affect Kv2.1 inactivation in ␤-cells from iPLA 2 ␤ ؊/؊ mice. Stably transfected INS-1 cells that overexpress iPLA 2 ␤ hydrolyze phospholipids more rapidly than control INS-1 cells and also exhibit an increase in the inactivation rate of the delayed rectifier currents. These results suggest that Kv2.1 currents could be dynamically modulated in the pancreatic islet ␤-cell by phospholipase-catalyzed hydrolysis of membrane phospholipids to yield non-esterified fatty acids, such as AA, that facilitate Ca 2؉ entry and insulin secretion.Glucose metabolism within the pancreatic islet ␤-cell generates a multitude of signals that regulate insulin secretion. Changes in the relative concentrations of the metabolites ATP and ADP cause ␤-cell depolarization via closure of ATP-sensitive potassium channels (K ATP ), 3 which results in activation of voltage-operated Ca 2ϩ channels, Ca 2ϩ influx, and insulin secretion (1). The extent of ␤-cell depolarization and insulin release are regulated in part by the activation of repolarizing ion channels, including the voltage-gated potassium channel, Kv2.1 (2-4). One mechanism employed by pancreatic ␤-cells to regulate the biophysical activity of the ion channels involved in insulin release involves hydrolysis of membrane phospholipids to yield mediators that include inositol triphosphates and free fatty acids (5-8).Pharmacologic, biochemical, and genetic evidence suggests that glucose-stimulated hydrolysis of esterified arachidonic acid from ␤-cell membrane phospholipids is required for physiological insulin secretion (7-25). Pancreatic islet ␤-cells contain high levels of arachidonic ac...

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Section: Discussionmentioning

confidence: 99%

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

Jacobson

Weber

Bao

et al. 2007

Journal of Biological Chemistry

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“…One possible alternative mechanism by which GPR40 may elevate [Ca i ] is offered by the demonstration that this receptor regulates the gating of voltage-dependent K-channels in β-cells [57]. These channels play a role in repolarisation of the plasma membrane during glucose stimulation and, as such, they facilitate the closure of voltage sensitive Ca channels and contribute to the lowering of cytosolic Ca levels.…”

Section: Signal Transduction Mechanisms Of Gpr40mentioning

confidence: 99%

“…These channels play a role in repolarisation of the plasma membrane during glucose stimulation and, as such, they facilitate the closure of voltage sensitive Ca channels and contribute to the lowering of cytosolic Ca levels. Feng et al [58] have presented evidence that the gating of voltage-gated K channels is impaired upon stimulation of GPR40 and that this then serves to prolong the opening of voltage sensitive Ca channels and to A c c e p t e d M a n u s c r i p t maintain cytosolic Ca at an elevated level. This action would, therefore, sustain [Ca i ] by influencing the influx of extracellular Ca rather than by promoting the mobilisation of Ca from within the ER.…”

Section: Signal Transduction Mechanisms Of Gpr40mentioning

confidence: 99%

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

Morgan¹,

Dhayal²

2009

Biochemical Pharmacology

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It is increasingly clear that some of the effects of both free and derivatised long chain fatty acids in pancreatic beta-cells are mediated by a group of G-protein coupled receptors. Some of these display close structural homology while others are more divergent. This Commentary reviews the expression and functional roles of three such molecules, GPR40, GPR119 and GPR120. GPR40 is the best characterised of this group and appears to mediate the acute stimulatory effects of long chain fatty acids on insulin secretion. GPR40 has also been proposed as a potential mediator of fatty acid toxicity but this is more controversial. GPR119 is also involved in stimulation of insulin secretion and responds primarily to ethanolamine derivatives of long chain fatty acids and also to some lysophospholipids rather than to free fatty acids. It may represent a useful target for the development of new insulin secretagogues aimed to enhance insulin release in patients with type 2 diabetes. GPR120 is the most enigmatic of the lipid responsive cell-surface receptors and its function remains to be established. It has been proposed to play a cytoprotective role in certain other cell types but it is unclear whether it fulfils a similar function in beta-cells.

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“…GPR40 is coupled to G αq with a subsequent increase in cytosolic Ca 2+ concentration (Itoh et al, 2003), although also a mechanism through activation of PLC has been proposed (Feng et al, 2006;Fujiwara et al, 2005;Shapiro et al, 2005). The possible role of GPR40 in insulin secretion has been studied using GPR40-deficient mice (GPR40-/-).…”

Section: Gpr40mentioning

confidence: 99%

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

Winzell

Åhrén

2007

Pharmacology & Therapeutics

161

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Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G-protein) coupled receptors (GPCRs). Examples of islet GPCRs are GPR40 and GPR119, which are GPCRs with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors

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

Cited by 118 publications

References 38 publications

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

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