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 Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic β-cells

1998 ◽  
Vol 274 (1) ◽  
pp. E38-E44 ◽  
Author(s):  
Eri Mukai ◽  
Hitoshi Ishida ◽  
Seika Kato ◽  
Yoshiyuki Tsuura ◽  
Shimpei Fujimoto ◽  
...  
Keyword(s):  
Metabolic Inhibition ◽  
K Channel ◽  
High Dose ◽  
Dependent Manner ◽  
Channel Activity ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Patch Clamp Technique ◽  
Channel Inhibition ◽  
Dose Dependent

The effect of metabolic inhibition on the blocking of β-cell ATP-sensitive K+ channels (KATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of KATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 μM) of ATP applied in the inside-out mode, KATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete KATP channel inhibition under 10 μM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits KATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, KATPchannel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic β-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.

scholarly journals Thiol oxidation by 2,2′-dithiodipyridine causes a reversible increase in cytoplasmic free Ca2+ concentration in pancreatic β-cells. Role for inositol 1,4,5-trisphosphate-sensitive Ca2+ stores

1997 ◽  
Vol 321 (2) ◽  
pp. 347-354 ◽  
Author(s):  
Md. Shahidul ISLAM ◽  
Henrik KINDMARK ◽  
Olof LARSSON ◽  
Per-Olof BERGGREN
Keyword(s):  
Ryanodine Receptors ◽  
Membrane Depolarization ◽  
Thiol Oxidation ◽  
High Concentration ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Patch Clamp Technique ◽  
Mitochondrial Inner Membrane ◽  
Patch Configuration ◽  
Ca2 Channels

2,2ƀ-Dithiodipyridine (2,2ƀ-DTDP), a reactive disulphide that mobilizes Ca2+ from ryanodine-sensitive Ca2+ stores in muscle, induced a biphasic increase in cytoplasmic free Ca2+ concentration ([Ca2+]i) in pancreatic α-cells loaded with fura 2. This increase consisted of an early transient followed by a second, slower, rise. The [Ca2+]i transient was dependent on extracellular Ca2+ and disappeared on treatment with nimodipine. The reactive disulphide caused plasma membrane depolarization, as studied by the perforated-patch configuration of the patch-clamp technique. Hence membrane depolarization and opening of the L-type voltage-gated Ca2+ channels were responsible for the first transient in [Ca2+]i. The second slower increase in [Ca2+]i was prolonged but readily reversed by the disulphide-reducing agent 1,4-dithiothreitol. This increase in [Ca2+]i was not decreased by nimodipine or by omission of extracellular Ca2+, but was eliminated when the Ins(1,4,5)P3-sensitive Ca2+ pool was first depleted by carbachol. Ryanodine or its α-alanyl analogue did not release Ca2+ from intracellular stores, and a high concentration of ryanodine did not inhibit Ca2+ release by 2,2ƀ-DTDP. The disulphide compound suppressed glucose metabolism and decreased the mitochondrial inner-membrane potential. We conclude that thiol oxidation by 2,2ƀ-DTDP affects Ca2+ homeostasis in α-cells by multiple mechanisms. However, unlike the situation in muscle, in α-cells 2,2ƀ-DTDP releases Ca2+ from intracellular pools by mechanisms that do not involve activation of ryanodine receptors. Instead, in these cells the Ins(1,4,5)P3-sensitive intracellular Ca2+ store comprises an alternative target for the Ca2+-mobilizing action of the reactive disulphide compound.

scholarly journals D2-Like Receptors Mediate Dopamine-Inhibited Insulin Secretion via Ion Channels in Rat Pancreatic β-Cells

2020 ◽  
Vol 11 ◽  
Author(s):  
Mengmeng Liu ◽  
Lele Ren ◽  
Xiangqin Zhong ◽  
Yaqin Ding ◽  
Tao Liu ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Ion Channels ◽  
Β Cells ◽  
Pancreatic Β Cells

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 Gating pore currents are defects in common with two Nav1.5 mutations in patients with mixed arrhythmias and dilated cardiomyopathy

2015 ◽  
Vol 145 (2) ◽  
pp. 93-106 ◽  
Author(s):  
Adrien Moreau ◽  
Pascal Gosselin-Badaroudine ◽  
Lucie Delemotte ◽  
Michael L. Klein ◽  
Mohamed Chahine
Keyword(s):  
Ion Channels ◽  
Dilated Cardiomyopathy ◽  
Patch Clamp Technique ◽  
Dynamic Simulations ◽  
Voltage Gated ◽  
Clinical Phenotypes ◽  
Pathological Mechanism ◽  
Cardiac Disorders ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

The gating pore current, also called omega current, consists of a cation leak through the typically nonconductive voltage-sensor domain (VSD) of voltage-gated ion channels. Although the study of gating pore currents has refined our knowledge of the structure and the function of voltage-gated ion channels, their implication in cardiac disorders has not been established. Two Nav1.5 mutations (R222Q and R225W) located in the VSD are associated with atypical clinical phenotypes involving complex arrhythmias and dilated cardiomyopathy. Using the patch-clamp technique, in silico mutagenesis, and molecular dynamic simulations, we tested the hypothesis that these two mutations may generate gating pore currents, potentially accounting for their clinical phenotypes. Our findings suggest that the gating pore current generated by the R222Q and R225W mutations could constitute the underlying pathological mechanism that links Nav1.5 VSD mutations with human cardiac arrhythmias and dilatation of cardiac chambers.

scholarly journals Mitochondrial Ion Channels in Pancreatic β‐cells: Novel Pharmacological Targets for the Treatment of Type 2 Diabetes

2020 ◽  
Author(s):  
Umberto De Marchi ◽  
Silvia Fernandez‐Martinez ◽  
Sergio Fuente ◽  
Andreas Wiederkehr ◽  
Jaime Santo‐Domingo
Keyword(s):  
Type 2 Diabetes ◽  
Ion Channels ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Pharmacological Targets

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 The Rab27a effector exophilin7 promotes fusion of secretory granules that have not been docked to the plasma membrane

2013 ◽  
Vol 24 (3) ◽  
pp. 319-330 ◽  
Author(s):  
Hao Wang ◽  
Ray Ishizaki ◽  
Jun Xu ◽  
Kazuo Kasai ◽  
Eri Kobayashi ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Knockout Mice ◽  
Secretory Granules ◽  
Small Gtpase ◽  
Membrane Phospholipids ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Insulin Granules ◽  
Insulin Exocytosis

Granuphilin, an effector of the small GTPase Rab27a, mediates the stable attachment (docking) of insulin granules to the plasma membrane and inhibits subsequent fusion of docked granules, possibly through interaction with a fusion-inhibitory Munc18-1/syntaxin complex. However, phenotypes of insulin exocytosis differ considerably between Rab27a- and granuphilin-deficient pancreatic β cells, suggesting that other Rab27a effectors function in those cells. We found that one of the putative Rab27a effector family proteins, exophilin7/JFC1/Slp1, is expressed in β cells; however, unlike granuphilin, exophilin7 overexpressed in the β-cell line MIN6 failed to show granule-docking or fusion-inhibitory activity. Furthermore, exophilin7 has no affinities to either Munc18-1 or Munc18-1–interacting syntaxin-1a, in contrast to granuphilin. Although β cells of exophilin7-knockout mice show no apparent abnormalities in intracellular distribution or in ordinary glucose-induced exocytosis of insulin granules, they do show impaired fusion in response to some stronger stimuli, specifically from granules that have not been docked to the plasma membrane. Exophilin7 appears to mediate the fusion of undocked granules through the affinity of its C2A domain toward the plasma membrane phospholipids. These findings indicate that the two Rab27a effectors, granuphilin and exophilin7, differentially regulate the exocytosis of either stably or minimally docked granules, respectively.

The ubiquitin–proteasome system regulates the stability and activity of the glucose sensor glucokinase in pancreatic β-cells

2013 ◽  
Vol 456 (2) ◽  
pp. 173-184 ◽  
Author(s):  
Anke Hofmeister-Brix ◽  
Sigurd Lenzen ◽  
Simone Baltrusch
Keyword(s):  
Protein Misfolding ◽  
Glucose Sensor ◽  
Ubiquitin Proteasome System ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulin Secreting Cells ◽  
Ubiquitin Proteasome ◽  
The Stability

The glucose phosphorylating enzyme glucokinase is regulated by the ubiquitin–proteasome system. Inhibition of the proteasome leads to reduced glucokinase activity, glucokinase protein misfolding and localization of glucokinase in aggresomes in insulin-secreting cells, pancreatic β-cells and hepatocytes.

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