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https://www.readbyqxmd.com/read/28092267/cryo-em-structure-of-the-atp-sensitive-potassium-channel-illuminates-mechanisms-of-assembly-and-gating
#1
Gregory M Martin, Craig Yoshioka, Emily A Rex, Jonathan F Fay, Qing Xie, Matthew R Whorton, James Z Chen, Show-Ling Shyng
KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic β-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6Å resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0)...
January 16, 2017: ELife
https://www.readbyqxmd.com/read/28003364/stromal-interaction-molecule-1-stim1-regulates-atp-sensitive-potassium-katp-and-store-operated-ca2-channels-in-min6-%C3%AE-cells
#2
Colin A Leech, Richard F Kopp, Heather A Nelson, Jyotirmoy Nandi, Michael W Roe
Stromal interaction molecule 1 (STIM1) regulates store-operated Ca(2+) entry (SOCE) and other ion channels, either as an endoplasmic reticulum (ER) Ca(2+) sensing protein or when present in the plasma membrane. However, the role of STIM1 in insulin-secreting β-cells is unresolved. We report that lowering expression of STIM1, the gene that encodes STIM1, in insulin-secreting MIN6 β-cells with RNA interference inhibits SOCE and ATP-sensitive K(+) (KATP) channel activation. The effects of STIM1 knockdown were reversed by transduction of MIN6 cells with an adenovirus gene shuttle vector that expressed human STIM1 Immunoprecipitation studies revealed that STIM1 binds to nucleotide binding fold-1 (NBF1) of the sulfonylurea receptor 1 (SUR1) subunit of the KATP channel...
December 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27995510/mechanisms-of-global-cerebral-edema-formation-in-aneurysmal-subarachnoid-hemorrhage
#3
Erik G Hayman, Aaron Wessell, Volodymyr Gerzanich, Kevin N Sheth, J Marc Simard
A growing body of clinical literature emphasizes the impact of cerebral edema in early brain injury following aneurysmal subarachnoid hemorrhage (aSAH). Aneurysm rupture itself initiates global cerebral edema in up to two thirds of cases. Although cerebral edema is not a universal feature of aSAH, it portends a poor clinical course, with quantitative analysis revealing a direct correlation between cerebral edema and poor outcome, including mortality and cognitive deficits. Mechanistically, global cerebral edema has been linked to global ischemia at the time of aneurysm rupture, dysfunction of autoregulation, blood breakdown products, neuroinflammation, and hyponatremia/endocrine abnormalities...
December 19, 2016: Neurocritical Care
https://www.readbyqxmd.com/read/27956473/diabetes-induced-by-gain-of-function-mutations-in-the-kir6-1-subunit-of-the-katp-channel
#4
Maria S Remedi, Jonathan B Friedman, Colin G Nichols
Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered...
January 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/27934605/generation-of-an-abcc8-heterozygous-mutation-human-embryonic-stem-cell-line-using-crispr-cas9
#5
Dongsheng Guo, Haikun Liu, Ge Gao, Aynisahan Ruzi, Kepin Wang, Han Wu, Keyu Lai, Yanli Liu, Fan Yang, Liangxue Lai, Yin-Xiong Li
The gene of ATP-binding cassette subfamily C member 8 (Abcc8) is cytogenetically located at 11p15.1 and encodes the sulfonylurea receptor (SUR1). SUR1 is a subunit of ATP-sensitive potassium channel (KAPT) in the β-cell regulating insulin secretion. Mutations of ABCC8 are responsible for congenital hyperinsulinism (CHI). Here we reported that an Abcc8 heterozygous mutant cell line was generated by CRISPR/Cas9 technique with 1bp insertion resulting in abnormal splicing on human embryonic stem cell line H1. The phenotypic characteristics of this cell line reveal defective KATP channel and diazoxide-responsive that provides ideal model for molecular pathology research and drug screening for CHI...
November 5, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27934599/generation-of-an-abcc8-homozygous-mutation-human-embryonic-stem-cell-line-using-crispr-cas9
#6
Dongsheng Guo, Haikun Liu, Ge Gao, Aynisahan Ruzi, Kepin Wang, Han Wu, Keyu Lai, Yanli Liu, Fan Yang, Liangxue Lai, Yin-Xiong Li
The gene of ATP-binding cassette subfamily C member 8 (Abcc8) is cytogenetically located at 11p15.1 and encodes the sulfonylurea receptor (SUR1). SUR1 is a subunit of ATP-sensitive potassium channel (KAPT) in the β-cell regulating insulin secretion. Mutations of ABCC8 are responsible for congenital hyperinsulinism (CHI). Here we generated an Abcc8 homozygous mutant cell line by CRISPR/Cas9 technique with 22bp deletion resulting in abnormal splicing on human embryonic stem cell line H1. The phenotypic characteristics of this cell line reveal defective KATP channel and diazoxide-unresponsive that provides an ideal model for molecular pathology research and drug screening for CHI...
November 9, 2016: Stem Cell Research
https://www.readbyqxmd.com/read/27884343/increased-tolerance-to-stress-in-cardiac-expressed-gain-of-function-of-adenosine-triphosphate-sensitive-potassium-channel-subunit-kir6-1
#7
Matthew C Henn, M Burhan Janjua, Haixia Zhang, Evelyn M Kanter, Carol M Makepeace, Richard B Schuessler, Colin G Nichols, Jennifer S Lawton
BACKGROUND: The adenosine triphosphate-sensitive potassium (KATP) channel opener diazoxide (DZX) prevents myocyte volume derangement and reduced contractility secondary to stress. KATP channels are composed of pore-forming (Kir6.1 or Kir6.2) and regulatory (sulfonylurea receptor, SUR1 or SUR2) subunits. Gain of function (GOF) of Kir6.1 subunits has been implicated in cardiac pathology in Cantu syndrome in humans (cardiomegaly, lymphedema, and pericardial effusions). We hypothesized that GOF of Kir6...
December 2016: Journal of Surgical Research
https://www.readbyqxmd.com/read/27807801/role-of-glibenclamide-in-brain-injury-after-intracerebral-hemorrhage
#8
Bing Jiang, Lin Li, Qianwei Chen, Yihao Tao, Liming Yang, Bo Zhang, John H Zhang, Hua Feng, Zhi Chen, Jun Tang, Gang Zhu
Brain edema following intracerebral hemorrhage (ICH) causes severe secondary brain injury, and no efficient pharmacological preventions are available. The present study was designed to demonstrate the neuroprotective effects of glibenclamide on brain edema and key factors of the blood-brain barrier (BBB). The study was divided into two parts. First, we utilized an autoblood-induced rat model to investigate the expression of sulfonylurea receptor 1 (Sur1). Second, rats were randomized into sham, vehicle, and glibenclamide groups...
November 3, 2016: Translational Stroke Research
https://www.readbyqxmd.com/read/27764176/a-novel-diphenylthiosemicarbazide-is-a-potential-insulin-secretagogue-for-anti-diabetic-agen
#9
Kenji Sugawara, Kohei Honda, Yoshie Reien, Norihide Yokoi, Chihiro Seki, Harumi Takahashi, Kohtaro Minami, Ichiro Mori, Akio Matsumoto, Haruaki Nakaya, Susumu Seino
Insulin secretagogues are used for treatment of type 2 diabetes. We attempted to discover novel small molecules to stimulate insulin secretion by using in silico similarity search using sulfonylureas as query, followed by measurement of insulin secretion. Among 38 compounds selected by in silico similarity search, we found three diphenylsemicarbazides and one quinolone that stimulate insulin secretion. We focused on compound 8 (C8), which had the strongest insulin-secreting effect. Based on the structure-activity relationship of C8-derivatives, we identified diphenylthiosemicarbazide (DSC) 108 as the most potent secretagogue...
2016: PloS One
https://www.readbyqxmd.com/read/27760384/chronic-intermittent-hybobaric-hypoxia-protects-against-cerebral-ischemia-via-modulation-of-mitokatp
#10
Shixiao Zhang, Zan Guo, Shijie Yang, Huijuan Ma, Congrui Fu, Sheng Wang, Yi Zhang, Yixian Liu, Jie Hu
OBJECTIVE: Providing adequate protection against cerebral ischemia remains an unrealized goal. The present study was aimed at testing whether chronic intermittent hypobaric hypoxia (CIHH) would have protective effects against cerebral ischemia and investigating the potential role of mitochondrial membrane ATP-sensitive potassium channel (mitoKATP) in this effect. METHODS: Ischemia was induced in rats by occlusion of bilateral common carotid arteries for 8min on day 2 after bilateral vertebral arteries were permanently electrocauterized and CIHH was simulated in a hypoxic chamber...
December 2, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27736926/calbindin-d9k-ablation-disrupt-glucose-pancreatic-insulin-homeostasis
#11
Changhwan Ahn, Dongoh Lee, Jae-Hwan Lee, Hyun Yang, Beum-Soo An, Eui-Bae Jeung
It has been proposed that cellular Ca2+ signals activate hormone secretion. In pancreatic β cells, which produce insulin, Ca2+ signals have been known to contribute to insulin secretion. Prior to this study, we confirmed that insulin-secreting β cells express CaBP-9k, and assumed that CaBP-9k play a role in β cell insulin synthesis or secretion. Using CaBP-9k knock out (KO) mice, we demonstrated that ablation of CaBP-9k causes reducing insulin secretion and increasing serum glucose. To compare the role of CaBP-9k with pathophysiological conditions, we exposed wild-type and CaBP-9k KO mice to hypoxic conditions for 10 days...
2016: PloS One
https://www.readbyqxmd.com/read/27693800/effects-of-zd0947-a-novel-and-potent-atp-sensitive-k-channel-opener-on-smooth-muscle-type-atp-sensitive-k-channels
#12
Keisuke Mori, Yoshio Yamashita, Noriyoshi Teramoto
The effects of ZD0947, a novel ATP-sensitive K(+) channel (KATP channel) opener, on the activity of reconstituted KATP channels were investigated using cell-attached recordings. KATP channels were studied in HEK 293 cells by co-expression of inwardly rectifying-6 family K(+) channel subunits (Kir6.x: Kir6.1 and Kir6.2) with 3 different types of sulphonylurea receptors (SUR.x: SUR1, SUR2A and SUR2B). ZD0947 (100µM) activated SUR2B/Kir6.2 channels in a concentration-dependent manner, but caused only weak activation of SUR1/Kir6...
November 15, 2016: European Journal of Pharmacology
https://www.readbyqxmd.com/read/27677908/abcc8-single-nucleotide-polymorphisms-are-associated-with-cerebral-edema-in-severe-tbi
#13
Ruchira M Jha, Ava M Puccio, David O Okonkwo, Benjamin E Zusman, Seo-Young Park, Jessica Wallisch, Philip E Empey, Lori A Shutter, Robert S B Clark, Patrick M Kochanek, Yvette P Conley
OBJECTIVE: Cerebral edema (CE) in traumatic brain injury (TBI) is the consequence of multiple underlying mechanisms and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for sulfonylurea receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNPs) are predictive of CE...
September 27, 2016: Neurocritical Care
https://www.readbyqxmd.com/read/27646472/activation-of-atp-sensitive-potassium-channels-enhances-dmt1-mediated-iron-uptake-in-sk-n-sh-cells-in-vitro
#14
Xixun Du, Huamin Xu, Limin Shi, Zhifeng Jiang, Ning Song, Hong Jiang, Junxia Xie
Iron importer divalent metal transporter 1 (DMT1) plays a crucial role in the nigal iron accumulation in Parkinson's disease (PD). Membrane hyperpolarization is one of the factors that could affect its iron transport function. Besides iron, selective activation of the ATP-sensitive potassium (KATP) channels also contributes to the vulnerability of dopaminergic neurons in PD. Interestingly, activation of KATP channels could induce membrane hyperpolarization. Therefore, it is of vital importance to study the effects of activation of KATP channels on DMT1-mediated iron uptake function...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27618741/chronic-exposure-to-katp-channel-openers-results-in-attenuated-glucose-sensing-in-hypothalamic-gt1-7-neurons
#15
Elizabeth Haythorne, D Lee Hamilton, John A Findlay, Craig Beall, Rory J McCrimmon, Michael L J Ashford
Individuals with Type 1 diabetes (T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamic neurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (KATP) activity, with KATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia...
December 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27573238/pharmacological-correction-of-trafficking-defects-in-atp-sensitive-potassium-channels-caused-by-sulfonylurea-receptor-1-mutations
#16
Gregory M Martin, Emily A Rex, Prasanna Devaraneni, Jerod S Denton, Kara E Boodhansingh, Diva D DeLeon, Charles A Stanley, Show-Ling Shyng
ATP-sensitive potassium (KATP) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to β-cell membrane potential. Loss of KATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects...
October 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27562702/in%C3%A2-vitro-effect-of-nicorandil-on-the-carbachol-induced-contraction-of-the-lower-esophageal-sphincter-of-the-rat
#17
Tomonori Shimbo, Takeshi Adachi, Susumu Fujisawa, Mai Hongoh, Takayoshi Ohba, Kyoichi Ono
The lower esophageal sphincter (LES) is a specialized region of the esophageal smooth muscle that allows the passage of a swallowed bolus into the stomach. Nitric oxide (NO) plays a major role in LES relaxation. Nicorandil possesses dual properties of a NO donor and an ATP-sensitive potassium channel (KATP channel) agonist, and is expected to reduce LES tone. This study investigated the mechanisms underlying the effects of nicorandil on the LES. Rat LES tissues were placed in an organ bath, and activities were recorded using an isometric force transducer...
August 2016: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/27561267/evaluation-of-the-pharmacokinetics-of-glibenclamide-tablet-given-off-label-orally-to-children-suffering-from-neonatal-syndromic-hyperglycemia
#18
Naïm Bouazza, Zoubir Djerada, Claire Gozalo, Kanetee Busiah, Jacques Beltrand, Marianne Berdugo, Saik Urien, Jean-Marc Treluyer, Michel Polak
PURPOSE: Glibenclamide (Gb) is used in type II diabetes mellitus but also in the last 10 years, off label, in patients with neonatal syndromic hyperglycemia carrying a mutation of Kir6.2 or SUR1. No studies have reported Gb pharmacokinetics in children. In this study, oral Gb pharmacokinetics was investigated in children in order to describe the concentration time courses, the influence of covariates, and the relationships between drug concentrations and efficacy. METHODS: Gb concentrations were measured in 18 children after the switch from subcutaneous insulin to oral tablets of Gb (crushed tablets for 33 % of patients)...
November 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27560494/sur1-associated-mechanisms-are-not-involved-in-ischemic-optic-neuropathy-1-day-post-injury
#19
James D Nicholson, Yan Guo, Steven L Bernstein
Ischemia-reperfusion injury after central nervous system (CNS) injury presents a major health care challenge with few promising treatments. Recently, it has become possible to reduce edema after CNS injury by antagonizing a sulfonylurea receptor 1 (SUR1) regulated ion channel expressed after injury. SUR1 upregulation after injury is a necessary precondition for the formation of this channel, and has been implicated in white matter injury after clinical spinal cord trauma. Glibenclamide, an SUR1 antagonist, appears to have neuroprotective effect against cerebral stroke in an open-label small clinical trial and great effectiveness in reducing damage after varied experimental CNS injury models...
2016: PloS One
https://www.readbyqxmd.com/read/27428958/transcriptome-and-metabolome-analyses-of-glucosinolates-in-two-broccoli-cultivars-following-jasmonate-treatment-for-the-induction-of-glucosinolate-defense-to-trichoplusia-ni-h%C3%A3-bner
#20
Kang-Mo Ku, Talon M Becker, John A Juvik
Lepidopteran larvae growth is influenced by host plant glucosinolate (GS) concentrations, which are, in turn, influenced by the phytohormone jasmonate (JA). In order to elucidate insect resistance biomarkers to lepidopteran pests, transcriptome and metabolome analyses following JA treatments were conducted with two broccoli cultivars, Green Magic and VI-158, which have differentially induced indole GSs, neoglucobrassicin and glucobrassicin, respectively. To test these two inducible GSs on growth of cabbage looper (Trichoplusia ni), eight neonate cabbage looper larvae were placed onto each of three plants per JA treatments (0, 100, 200, 400 µM) three days after treatment...
July 15, 2016: International Journal of Molecular Sciences
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