scholarly journals Mutations of the Same Conserved Glutamate Residue in NBD2 of the Sulfonylurea Receptor 1 Subunit of the KATP Channel Can Result in Either Hyperinsulinism or Neonatal Diabetes

Diabetes ◽  
2011 ◽  
Vol 60 (6) ◽  
pp. 1813-1822 ◽  
Author(s):  
R. Mannikko ◽  
S. E. Flanagan ◽  
X. Sim ◽  
D. Segal ◽  
K. Hussain ◽  
...  
Keyword(s):  
Katp Channel ◽  
Neonatal Diabetes ◽  
Sulfonylurea Receptor ◽  
Sulfonylurea Receptor 1

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.

scholarly journals Neonatal Diabetes Caused by Mutations in Sulfonylurea Receptor 1: Interplay between Expression and Mg-Nucleotide Gating Defects of ATP-Sensitive Potassium Channels

2010 ◽  
Vol 31 (5) ◽  
pp. 779-779
Author(s):  
Qing Zhou ◽  
Intza Garin ◽  
Luis Castaño ◽  
Jesús Argente ◽  
Ma. Teresa Muñoz-Calvo ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Neonatal Diabetes ◽  
Sulfonylurea Receptor ◽  
Sulfonylurea Receptor 1

scholarly journals Noble Gas Xenon Is a Novel Adenosine Triphosphate-sensitive Potassium Channel Opener

2010 ◽  
Vol 112 (3) ◽  
pp. 623-630 ◽  
Author(s):  
Carsten Bantel ◽  
Mervyn Maze ◽  
Stefan Trapp
Keyword(s):  
Blood Brain Barrier ◽  
Adenosine Triphosphate ◽  
Katp Channel ◽  
Katp Channels ◽  
Brain Barrier ◽  
Hek293 Cells ◽  
Sulfonylurea Receptor ◽  
Channel Opener ◽  
Blood Brain ◽  
Sulfonylurea Receptor 1

Background Adenosine triphosphate-sensitive potassium (KATP) channels in brain are involved in neuroprotective mechanisms. Pharmacologic activation of these channels is seen as beneficial, but clinical exploitation by using classic K channel openers is hampered by their inability to cross the blood-brain barrier. This is different with the inhalational anesthetic xenon, which recently has been suggested to activate KATP channels; it partitions freely into the brain. Methods To evaluate the type and mechanism of interaction of xenon with neuronal-type KATP channels, these channels, consisting of Kir6.2 pore-forming subunits and sulfonylurea receptor-1 regulatory subunits, were expressed in HEK293 cells and whole cell, and excised patch-clamp recordings were performed. Results Xenon, in contrast to classic KATP channel openers, acted directly on the Kir6.2 subunit of the channel. It had no effect on the closely related, adenosine triphosphate (ATP)-regulated Kir1.1 channel and failed to activate an ATP-insensitive mutant version of Kir6.2. Furthermore, concentration-inhibition curves for ATP obtained from inside-out patches in the absence or presence of 80% xenon revealed that xenon reduced the sensitivity of the KATP channel to ATP. This was reflected in an approximately fourfold shift of the concentration causing half-maximal inhibition (IC50) from 26 +/- 4 to 96 +/- 6 microm. Conclusions Xenon represents a novel KATP channel opener that increases KATP currents independently of the sulfonylurea receptor-1 subunit by reducing ATP inhibition of the channel. Through this action and by its ability to readily partition across the blood-brain barrier, xenon has considerable potential in clinical settings of neuronal injury, including stroke.

scholarly journals Neonatal Diabetes Caused by Mutations in Sulfonylurea Receptor 1: Interplay between Expression and Mg-Nucleotide Gating Defects of ATP-Sensitive Potassium Channels

2010 ◽  
Vol 24 (10) ◽  
pp. 2070-2070
Author(s):  
Qing Zhou ◽  
Intza Garin ◽  
Luis Castaño ◽  
Jesús Argente ◽  
Ma. Teresa Muñoz-Calvo ◽  
...  
Keyword(s):  
Neonatal Diabetes ◽  
Katp Channels ◽  
Nucleotide Binding ◽  
Sulfonylurea Receptor ◽  
Channel Response ◽  
Potential Gain ◽  
Channel Expression ◽  
Transient Neonatal Diabetes ◽  
Sulfonylurea Receptor 1 ◽  
Diabetes Severity

Abstract Context: ATP-sensitive potassium (KATP) channels regulate insulin secretion by coupling glucose metabolism to β-cell membrane potential. Gain-of-function mutations in the sulfonylurea receptor 1 (SUR1) or Kir6.2 channel subunit underlie neonatal diabetes. Objective: The objective of the study was to determine the mechanisms by which two SUR1 mutations, E208K and V324M, associated with transient neonatal diabetes affect KATP channel function. Design: E208K or V324M mutant SUR1 was coexpressed with Kir6.2 in COS cells, and expression and gating properties of the resulting channels were assessed biochemically and electrophysiologically. Results: Both E208K and V324M augment channel response to MgADP stimulation without altering sensitivity to ATP4− or sulfonylureas. Surprisingly, whereas E208K causes only a small increase in MgADP response consistent with the mild transient diabetes phenotype, V324M causes a severe activating gating defect. Unlike E208K, V324M also impairs channel expression at the cell surface, which is expected to dampen its functional impact on β-cells. When either mutation was combined with a mutation in the second nucleotide binding domain of SUR1 previously shown to abolish Mg-nucleotide response, the activating effect of E208K and V324M was also abolished. Moreover, combination of E208K and V324M results in channels with Mg-nucleotide sensitivity greater than that seen in individual mutations alone. Conclusion: The results demonstrate that E208K and V324M, located in distinct domains of SUR1, enhance transduction of Mg-nucleotide stimulation from the SUR1 nucleotide binding folds to Kir6.2. Furthermore, they suggest that diabetes severity is determined by interplay between effects of a mutation on channel expression and channel gating.

Intellectual disability in KATP channel neonatal diabetes

2020 ◽  
Author(s):  
Svalastoga P ◽  
Sulen A ◽  
Fehn JR ◽  
Aukland SM ◽  
Irgens H ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Katp Channel ◽  
Neonatal Diabetes

scholarly journals Sulfonylurea Receptor 1 in Humans with Post-Traumatic Brain Contusions

2015 ◽  
Vol 32 (19) ◽  
pp. 1478-1487 ◽  
Author(s):  
Tamara Martínez-Valverde ◽  
Marian Vidal-Jorge ◽  
Elena Martínez-Saez ◽  
Lidia Castro ◽  
Fuat Arikan ◽  
...  
Keyword(s):  
Sulfonylurea Receptor ◽  
Post Traumatic ◽  
Sulfonylurea Receptor 1
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