ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis

Miki, Takashi; Liss, Birgit; Minami, Kohtaro; Shiuchi, Tetsuya; Saraya, Atsunori; Kashima, Yasushige; Horiuchi, Masatsugu; Ashcroft, Frances M.; Minokoshi, Yasuhiko; Roeper, Jochen; Seino, Susumu

doi:10.1038/87455

Cited by 477 publications

(364 citation statements)

References 47 publications

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“…rich with leptin receptors and glucose-responsive elements analogous to those of pancreatic beta cells (Yang et al, 1999;Miki et al, 2001;Evans et al, 2004;McCrimmon et al, 2004;Squires et al, 2005). Accordingly, the VMN mediates counter-regulatory responses to hypoglycemia and energy balance responses to leptin (Jacob et al, 1997;Satoh et al, 1997;Choi et al, 1999;Dube et al, 1999;Elias et al, 2000;Borg et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

Fekete

Inoue

Zhao

et al. 2006

Neuropsychopharmacol

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Brain corticotropin-releasing factor/urocortin (CRF/Ucn) systems are hypothesized to control feeding, with central administration of 'type 2' urocortins producing delayed anorexia. The present study sought to identify the receptor subtype, brain site, and behavioral mode of action through which Ucn 3 reduces nocturnal food intake in rats. Non-food-deprived male Wistar rats (n ¼ 176) were administered Ucn 3 into the lateral (LV) or fourth ventricle, or into the ventromedial or paraventricular nuclei of the hypothalamus (VMN, PVN) or the medial amygdala (MeA), regions in which Ucn 3 is expressed in proximity to CRF 2 receptors. LV Ucn 3 suppressed ingestion during the third-fourth post-injection hours. LV Ucn 3 anorexia was reversed by cotreatment with astressin 2 -B, a selective CRF 2 antagonist and not observed following equimole subcutaneous or fourth ventricle administration. Bilateral intra-VMN and intra-PVN infusion, more potently than LV infusion, reduced the quantity (57-73%) and duration of ingestion (32-68%) during the third-fourth post-infusion hours. LV, intra-PVN and intra-VMN infusion of Ucn 3 slowed the eating rate and reduced intake by prolonging the post-meal interval. Intra-VMN Ucn 3 reduced feeding bout size, and intra-PVN Ucn 3 reduced the regularity of eating from pellet to pellet. Ucn 3 effects were behaviorally specific, because minimal effective anorectic Ucn 3 doses did not alter drinking rate or promote a conditioned taste aversion, and site-specific, because intra-MeA Ucn 3 produced a nibbling pattern of more, but smaller meals without altering total intake. The results implicate the VMN and PVN of the hypothalamus as sites for Ucn 3-CRF 2 control of food intake.

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Section: Discussionmentioning

confidence: 99%

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

Fekete

Inoue

Zhao

et al. 2006

Neuropsychopharmacol

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“…However, K ATP channels in islet cells and L cells are involved in the release of hormones that modulate insulin secretion. Likewise, K ATP channels in ventromedial hypothalamic neurons appear to be involved in the counter-regulatory response to glucose (Miki et al, 2001), and those of the substantia nigra may be involved in movement control (Roeper et al, 1990). Since Kir6.2 is the binding site for haloperidol, it might exert unspecific side effects by inhibiting different K ATP channels in a wide range of tissues.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ATP‐sensitive potassium channels by haloperidol

Yang

Proks

Ashcroft

et al. 2004

British J Pharmacology

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1 Chronic haloperidol treatment has been associated with an increased incidence of glucose intolerance and type-II diabetes mellitus. We studied the effects of haloperidol on native ATP-sensitive potassium (K ATP ) channels in mouse pancreatic b cells and on cloned Kir6.2/SUR1 channels expressed in HEK293 cells. 2 The inhibitory effect of haloperidol on the K ATP channel was not mediated via the D2 receptor signaling pathway, as both D2 agonists and antagonists blocked the channel. 3 K ATP currents were studied using the patch-clamp technique in whole-cell and outside-out patch configurations. Addition of haloperidol to the extracellular solution inhibited the K ATP conductance immediately, in a reversible and voltage-independent manner. Haloperidol did not block the channel when applied intracellularly in whole-cell recordings. 4 Haloperidol blocked cloned Kir6.2/SUR1 and Kir6.2DC36 K ATP channels expressed in HEK cells. This suggests that the drug interacts with the Kir6.2 subunit of the channel. 5 The IC 50 for inhibition of the K ATP current by haloperidol was 1.6 mM in 2 mM extracellular K þ concentration ([K þ ] o ) and increased to 23.9 mM in 150 mM [K þ ] o . The Hill coefficient was close to unity, suggesting that the binding of a single molecule of haloperidol is sufficient to close the channel. 6 Haloperidol block of K ATP channels may contribute to the side effects of this drug when used therapeutically.

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“…K ATP channels exist as oligomeric structures comprising four copies each of a K + channel of the inward rectifier class (Kir6.2), which form the channel pore, and four sulfonylurea receptor-1 (SUR1) subunits [3]. Closure of K ATP channels is pivotal to the actions of both nutrient secretagogues and sulfonylureas; changes in the activity of either subunit leads to defective insulin secretion and glucose homeostasis in rodents [5][6][7]. Moreover, mutations in either subunit are a common cause of hyperinsulinism in infancy [8,9], whilst polymorphisms in the KCNJ11 gene, which generate a form (E23K) of Kir6.2 with decreased activity, are linked to type 2 diabetes in human populations [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Intracellular ATP-sensitive K+ channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis

et al. 2006

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Aims/hypothesis: ATP-sensitive K + (K ATP ) channels located on the beta cell plasma membrane play a critical role in regulating insulin secretion and are targets for the sulfonylurea class of antihyperglycaemic drugs. Recent reports suggest that these channels may also reside on insulin-containing dense-core vesicles and mitochondria. The aim of this study was to explore these possibilities and to test the hypothesis that vesicle-resident channels play a role in the control of organellar Ca 2+ concentration or pH. Methods: To quantify the subcellular distribution of the pore-forming subunit Kir6.2 and the sulfonylurea binding subunit SUR1 in isolated mouse islets and clonal pancreatic MIN6 beta cells, we used four complementary techniques: immunoelectron microscopy, density gradient fractionation, vesicle immunopurification and fluorescence-activated vesicle isolation. Intravesicular and mitochondrial concentrations of free Ca 2+ were measured in intact or digitonin-permeabilised MIN6 cells using recombinant, targeted aequorins, and intravesicular pH was measured with the recombinant fluorescent probe pHluorin. Results: SUR1 and Kir6.2 immunoreactivity were concentrated on dense-core vesicles and on vesicles plus the endoplasmic reticulum/Golgi network, respectively, in both islets and MIN6 cells. Reactivity to neither subunit was detected on mitochondria. Glibenclamide, tolbutamide and diazoxide all failed to affect Ca 2+ uptake into mitochondria, and K ATP channel regulators had no significant effect on intravesicular free Ca 2+ concentrations or vesicular pH. Conclusions/Interpretation: A significant proportion of Kir6.2 and SUR1 subunits reside on insulin-secretory vesicles and the distal secretory pathway in mouse beta cells but do not influence intravesicular ion homeostasis. We propose that densecore vesicles may serve instead as sorting stations for the delivery of channels to the plasma membrane.

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ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis

Cited by 477 publications

References 47 publications

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

Inhibition of ATP‐sensitive potassium channels by haloperidol

Intracellular ATP-sensitive K+ channels in mouse pancreatic beta cells: against a role in organelle cation homeostasis

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