scholarly journals Familial Leucine-Sensitive Hypoglycemia of Infancy Due to a Dominant Mutation of the β-Cell Sulfonylurea Receptor

2004 ◽  
Vol 89 (9) ◽  
pp. 4450-4456 ◽  
Author(s):  
Sheela N. Magge ◽  
Show-Ling Shyng ◽  
Courtney MacMullen ◽  
Linda Steinkrauss ◽  
Arupa Ganguly ◽  
...  
Keyword(s):  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Dominant Mutation ◽  
Leucine Sensitive Hypoglycemia

scholarly journals Direct photoaffinity labeling of the putative sulfonylurea receptor in rat β-cell tumor membranes by [3H]glibenclamide

FEBS Letters ◽  
1988 ◽  
Vol 229 (2) ◽  
pp. 355-359 ◽  
Author(s):  
Werner Kramer ◽  
Raymond Oekonomopulos ◽  
Jürgen Pünter ◽  
Hans-Dieter Summ
Keyword(s):  
Photoaffinity Labeling ◽  
Cell Tumor ◽  
Sulfonylurea Receptor ◽  
Β Cell

scholarly journals Differential interaction of glimepiride and glibenclamide with the β-cell sulfonylurea receptor I. Binding characteristics

1994 ◽  
Vol 1191 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Günter Müller ◽  
Detlev Hartz ◽  
Jürgen Pünter ◽  
Raymond Ökonomopulos ◽  
Werner Kramer
Keyword(s):  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Binding Characteristics ◽  
Differential Interaction

scholarly journals Sulfonylureas suppress the stimulatory action of Mg-nucleotides on Kir6.2/SUR1 but not Kir6.2/SUR2A KATP channels: A mechanistic study

2014 ◽  
Vol 144 (5) ◽  
pp. 469-486 ◽  
Author(s):  
Peter Proks ◽  
Heidi de Wet ◽  
Frances M. Ashcroft
Keyword(s):  
Katp Channel ◽  
Neonatal Diabetes ◽  
Katp Channels ◽  
Nucleotide Binding ◽  
Mechanistic Study ◽  
Xenopus Laevis Oocytes ◽  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Stimulatory Action ◽  
Channel Inhibition

Sulfonylureas, which stimulate insulin secretion from pancreatic β-cells, are widely used to treat both type 2 diabetes and neonatal diabetes. These drugs mediate their effects by binding to the sulfonylurea receptor subunit (SUR) of the ATP-sensitive K+ (KATP) channel and inducing channel closure. The mechanism of channel inhibition is unusually complex. First, sulfonylureas act as partial antagonists of channel activity, and second, their effect is modulated by MgADP. We analyzed the molecular basis of the interactions between the sulfonylurea gliclazide and Mg-nucleotides on β-cell and cardiac types of KATP channel (Kir6.2/SUR1 and Kir6.2/SUR2A, respectively) heterologously expressed in Xenopus laevis oocytes. The SUR2A-Y1206S mutation was used to confer gliclazide sensitivity on SUR2A. We found that both MgATP and MgADP increased gliclazide inhibition of Kir6.2/SUR1 channels and reduced inhibition of Kir6.2/SUR2A-Y1206S. The latter effect can be attributed to stabilization of the cardiac channel open state by Mg-nucleotides. Using a Kir6.2 mutation that renders the KATP channel insensitive to nucleotide inhibition (Kir6.2-G334D), we showed that gliclazide abolishes the stimulatory effects of MgADP and MgATP on β-cell KATP channels. Detailed analysis suggests that the drug both reduces nucleotide binding to SUR1 and impairs the efficacy with which nucleotide binding is translated into pore opening. Mutation of one (or both) of the Walker A lysines in the catalytic site of the nucleotide-binding domains of SUR1 may have a similar effect to gliclazide on MgADP binding and transduction, but it does not appear to impair MgATP binding. Our results have implications for the therapeutic use of sulfonylureas.

Short-term intermittent exposure to diazoxide improves functional performance of β-cells in a high-glucose environment

2004 ◽  
Vol 287 (6) ◽  
pp. E1202-E1208 ◽  
Author(s):  
Hiroyasu Yoshikawa ◽  
Zuheng Ma ◽  
Anneli Björklund ◽  
Valdemar Grill
Keyword(s):  
High Glucose ◽  
Functional Performance ◽  
Uncoupling Protein ◽  
Insulin Response ◽  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Short Term ◽  
Beneficial Effects ◽  
Voltage Dependent ◽  
Associated Proteins

Prolonged periods of “β-cell rest” exert beneficial effects on insulin secretion from pancreatic islets subjected to a high-glucose environment. Here, we tested for effects of short-term intermittent rest achieved by diazoxide. Rat islets were cultured for 48 h with 27 mmol/l glucose alone, with diazoxide present for 2 h every 12 h or with continuous 48-h presence of diazoxide. Both protocols with diazoxide enhanced the postculture insulin response to 27 mmol/l glucose, to 200 μmol/l tolbutamide, and to 20 mmol/l KCl. Intermittent diazoxide did not affect islet insulin content and enhanced only KATP-dependent secretion, whereas continuous diazoxide increased islet insulin contents and enhanced both KATP-dependent and -independent secretory effects of glucose. Intermittent and continuous diazoxide alike increased postculture ATP-to-ADP ratios, failed to affect [14C]glucose oxidation, but decreased oxidation of [14C]oleate. Neither of the two protocols affected gene expression of the ion channel-associated proteins Kir6.2, sulfonylurea receptor 1, voltage-dependent calcium channel-α1, or Kv2.1. Continuous, but not intermittent, diazoxide decreased significantly mRNA for uncoupling protein-2. A 2-h exposure to 20 mmol/l KCl or 10 μmol/l cycloheximide abrogated the postculture effects of intermittent, but not of continuous, diazoxide. Intermittent diazoxide decreased islet levels of the SNARE protein SNAP-25, and KCl antagonized this effect. Thus short-term intermittent diazoxide treatment has beneficial functional effects that encompass some but not all characteristics of continuous diazoxide treatment. The results support the soundness of intermittent β-cell rest as a treatment strategy in type 2 diabetes.

Arrhythmia susceptibility and premature death in transgenic mice overexpressing both SUR1 and Kir6.2[ΔN30,K185Q] in the heart

2007 ◽  
Vol 293 (1) ◽  
pp. H836-H845 ◽  
Author(s):  
Thomas P. Flagg ◽  
Brian Patton ◽  
Ricard Masia ◽  
Carrie Mansfield ◽  
Anatoli N. Lopatin ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Premature Death ◽  
Sulfonylurea Receptor ◽  
Wild Type ◽  
Membrane Excitability ◽  
Β Cell ◽  
Isolated Hearts ◽  
High Level ◽  
Conscious Animals

Sarcolemmal ATP-sensitive potassium (KATP) channels are activated after pathological depletion of intracellular ATP, unlike their pancreatic β-cell counterparts, which dynamically regulate membrane excitability in response to changes in blood glucose. We recently engineered a series of transgenic (TG) mice overexpressing an ATP-insensitive inward rectifying K+ channel protein (Kir)6.2 mutant (Kir6.2[ΔN30,K185Q]) or the accessory sulfonylurea receptor (SUR)2A (FLAG-SUR2A) or SUR1 (FLAG-SUR1) subunits of the KATP channel, under transcriptional control of the α-myosin heavy chain promoter. In the present study, we generated double transgenic (DTG) animals overexpressing both Kir6.2[ΔN30,K185Q] and FLAG-SUR1 or FLAG-SUR2A and examined the effects on cardiac excitability in vivo. No animals expressing both FLAG-SUR1 and Kir6.2[ΔN30,K185Q] transgenes at a high level were obtained. DTG mice expressing one transgene at a high level and the other at a lower level are born, but they die prematurely. Electrocardiographic analysis of both anesthetized and conscious animals revealed a constellation of arrhythmias in DTG animals, but not in wild-type or single TG littermates. The proarrhythmic effect of the transgene combination is intrinsic to the myocardium, since it persists in isolated hearts. Importantly, this effect is specific for SUR1-expressing DTG animals: DTG animals expressing both Kir6.2[ΔN30,K185Q] and FLAG-SUR2A at high levels exhibit neither impaired survival nor increased arrhythmia frequency, even with both subunits expressed at high levels. In demonstrating the profound arrhythmic consequences of KATP channels comprised of SUR1 and Kir6.2[ΔN30,K185Q] in the myocardium specifically, the results highlight the critical differential activation of SUR1 versus SUR2A, and indicate that expression of hyperactive KATP in the heart is likely to be proarrhythmic.

scholarly journals Determination of the molecular mass of the native β-cell sulfonylurea receptor

FEBS Letters ◽  
1994 ◽  
Vol 338 (1) ◽  
pp. 98-102 ◽  
Author(s):  
Jacqueline M. Skeer ◽  
Pilar Dégano ◽  
Barbara Coles ◽  
Michel Potier ◽  
Frances M. Ashcroft ◽  
...  
Keyword(s):  
Molecular Mass ◽  
Sulfonylurea Receptor ◽  
Β Cell

scholarly journals The Actions of a Novel Potent Islet β-Cell–Specific ATP-Sensitive K+Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1

Diabetes ◽  
2007 ◽  
Vol 56 (8) ◽  
pp. 2124-2134 ◽  
Author(s):  
Betty Ng ◽  
Youhou Kang ◽  
Chadwick L. Elias ◽  
Yan He ◽  
Huanli Xie ◽  
...  
Keyword(s):  
K Channel ◽  
Sulfonylurea Receptor ◽  
Β Cell ◽  
Syntaxin 1A ◽  
Channel Opener ◽  
Sulfonylurea Receptor 1 ◽  
K Channel Opener
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