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Cited by 282Ion channel regulation and functionAdenosine and Purinergic SignalingPancreatic function and diabetes

Regulation of KATP Channel Activity by Diazoxide and MgADP

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Shyng, S.-L., Ferrigni, T., Nichols, C.G.·1997·The Journal of General Physiology
DOI 10.1085/jgp.110.6.643PMC PMC2229399
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Abstract

KATP channels were reconstituted in COSm6 cells by coexpression of the sulfonylurea receptor SUR1 and the inward rectifier potassium channel Kir6.2. The role of the two nucleotide binding folds of SUR1 in regulation of KATP channel activity by nucleotides and diazoxide was investigated. Mutations in the linker region and the Walker B motif (Walker, J.E., M.J. Saraste, M.J. Runswick, and N.J. Gay. 1982. EMBO [Eur. Mol. Biol. Organ.] J. 1:945–951) of the second nucleotide binding fold, including G1479D, G1479R, G1485D, G1485R, Q1486H, and D1506A, all abolished stimulation by MgADP and diazoxide, with the exception of G1479R, which showed a small stimulatory response to diazoxide. Analogous mutations in the first nucleotide binding fold, including G827D, G827R, and Q834H, were still stimulated by diazoxide and MgADP, but with altered kinetics compared with the wild-type channel. None of the mutations altered the sensitivity of the channel to inhibition by ATP4−. We propose a model in which SUR1 sensitizes the KATP channel to ATP inhibition, and nucleotide hydrolysis at the nucleotide binding folds blocks this effect. MgADP and diazoxide are proposed to stabilize this desensitized state of the channel, and mutations at the nucleotide binding folds alter the response of channels to MgADP and diazoxide by altering nucleotide hydrolysis rates or the coupling of hydrolysis to channel activation.

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  • Diazoxide mediates its effect by binding to SUR1, and its action requires intact nucleotide-binding domains and the presence of MgADP or MgATP.

    “The KATP channel activator diazoxide also mediates its effect by binding to SUR1 (232). Its binding site is still unknown. Interestingly, diazoxide action requires the presence of intact nucleotide-binding domains and the presence of MgADP (or MgATP) (232, 621).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [621]

    The Results sections on nucleotide requirements and SUR1 mutations support a role for Mg2+-bound nucleotides and the nucleotide-binding folds in diazoxide stimulation. But the Discussion section on nucleotide gating says the SUR1 structure that binds diazoxide has not been identified and only speculates that diazoxide binds at the nucleotide-binding folds; it does not establish that diazoxide acts by binding SUR1. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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  • SUR1 regulates the activity of the Kir6.2 pore, endowing it with sensitivity to inhibitory sulfonylurea drugs, K+ channel openers such as diazoxide, and stimulatory effects of Mg-nucleotides.

    “Instead, it regulates the activity of the Kir6.2 pore, endowing it with sensitivity to inhibitory sulfonylurea drugs (hence its name), to K+ channel openers such as diazoxide, and to the stimulatory effects of Mg-nucleotides (5, 232, 621, 698).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [621]

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Research works printed but not linked: 45

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Authors
Shyng, S.-L., Ferrigni, T., & Nichols, C. G.
Affiliations
Washington University in St. Louis (US)
ORCID
Venue
The Journal of General Physiology
Publisher
Rockefeller University Press
Published
1997-12-01
Volume
110
Issue
6
Pages
643-654
ISSN
  • 0022-1295 (ISSN-L)
  • 1540-7748
DOI
10.1085/jgp.110.6.643
PMC
PMC2229399
OpenAlex
W2129668416
Cited by
282
References
1
Citations by year
2026: 3 · 2025: 1 · 2024: 6 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 5 · 2017: 6 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 12 · 2012: 16
FWCI
7.87
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of General Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (HL 45742, R01HL045742)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
ATP-sensitive potassium channels, diazoxide, MgADP, Kir6.2, nucleotide binding fold, Walker B motif, nucleotide hydrolysis, ATP inhibition, channel desensitization, channel gating
MeSH terms
Adenosine Diphosphate, Adenosine Triphosphate, Animals, Antihypertensive Agents, Diazoxide, Hydrolysis, Kinetics, Magnesium, Receptors, Drug, Sulfonylurea Compounds, Potassium Channels, Ion Channel Gating, Mutagenesis, Site-Directed, Protein Folding, Patch-Clamp Techniques, ATP-Binding Cassette Transporters, COS Cells, Potassium Channels, Inwardly Rectifying, Sulfonylurea Receptors

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