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Cited by 22Ion channel regulation and functionPancreatic function and diabetesCardiac electrophysiology and arrhythmias

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

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Proks, Peter, de Wet, Heidi, Ashcroft, Frances M.·2014·Journal of General Physiology
DOI 10.1085/jgp.201411222PMC PMC4210431
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Abstract

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.

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  • Sulfonylureas act as partial antagonists at SUR1 in excised patches but fully block the KATP current in whole cells because they also prevent MgADP activation of the β-cell KATP channel.

    “Sulfonylureas act as partial antagonists at SUR1, as in excised patches they only inhibit the channel by a maximum of ~60%. In the whole-cell configuration, however, they fully block the KATP current. This discrepancy is due to the fact that sulfonylureas also prevent MgADP activation of the β-cell KATP channel (233, 524).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [524]

    The Introduction describes sulfonylureas as partial antagonists whose high-affinity inhibition reaches about 50–80%. The Results (Nucleotide modulation of sulfonylurea inhibition) show that gliclazide abolishes MgADP activation of Kir6.2/SUR1 channels, enhancing inhibition. The paper’s experiments used inside-out patches (Materials and Methods, Electrophysiology); the passages do not establish the claimed full block of KATP current in whole cells. (LLM, conf=0.85)

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Authors
Proks, P., de Wet, H., & Ashcroft, F. M.
Affiliations
  • University of Oxford (GB)
  • Oxford Centre for Gene Function 1 and 2
Corresponding author
Ashcroft, Frances M.
ORCID
Venue
Journal of General Physiology
Publisher
Rockefeller University Press
Published
2014-10-27
Volume
144
Issue
5
Pages
469-486
ISSN
  • 0022-1295 (ISSN-L)
  • 1540-7748
DOI
10.1085/jgp.201411222
PMC
PMC4210431
OpenAlex
W2116624566
Cited by
22
References
5
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 5
FWCI
1.50
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of General Physiology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
Wellcome Trust (089795/Z/09/Z, 084655)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
sulfonylureas, gliclazide, ATP-sensitive potassium channels, MgADP, MgATP, sulfonylurea receptor, channel inhibition mechanism, nucleotide binding, pancreatic beta cells, cardiac KATP channels, insulin secretion
MeSH terms
Kcnj11 Channel, Adenosine Diphosphate, Adenosine Triphosphate, Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Gliclazide, Humans, Molecular Sequence Data, Protein Binding, Xenopus, Ion Channel Gating, Amino Acid Motifs, Potassium Channels, Inwardly Rectifying, Insulin-Secreting Cells, Rats, Sulfonylurea Receptors

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