The essential role of the Walker A motifs of SUR1 in K‐ATP channel activation by Mg‐ADP and diazoxide
Open accessAbstract
The ATP-sensitive K-channel (K-ATP channel) plays a key role in insulin secretion from pancreatic beta-cells. It is closed by glucose metabolism, which stimulates insulin secretion, and opened by the drug diazoxide, which inhibits insulin release. Metabolic regulation is mediated by changes in ATP and Mg-ADP, which inhibit and potentiate channel activity, respectively. The beta-cell K-ATP channel consists of a pore-forming subunit, Kir6.2, and a regulatory subunit, SUR1. We have mutated (independently or together) two lysine residues in the Walker A (W(A)) motifs of the first (K719A) and second (K1384M) nucleotide-binding domains (NBDs) of SUR1. These mutations are expected to inhibit nucleotide hydrolysis. Our results indicate that the W(A) lysine of NBD1 (but not NBD2) is essential for activation of K-ATP currents by diazoxide. The potentiatory effects of Mg-ADP required the presence of the W(A) lysines in both NBDs. Mutant currents were slightly more sensitive to ATP than wild-type currents. Metabolic inhibition led to activation of wild-type and K1384M currents, but not K719A or K719A/K1384M currents, suggesting that there may be a factor in addition to ATP and ADP which regulates K-ATP channel activity.
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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 [232]
The Introduction (page unavailable) says SUR1 confers diazoxide sensitivity, but does not establish that diazoxide binds directly to SUR1. The Abstract and Discussion (pages unavailable) report that the Walker A lysine of SUR1’s first nucleotide-binding domain is essential for diazoxide activation, whereas the second is not; the Introduction and Effects of Mg-ADP describe activity in the presence of Mg-ATP or Mg-ADP. Thus the nucleotide condition is supported, but the claim that both domains must be intact overstates the findings. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSUR1 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 [232]
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Self-citationSulfonylurea Stimulation of Insulin Secretion
Proks, P., Reimann, F., Green, N., Gribble, F., & Ashcroft, F. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s368 · Cited by 510 · see citing works
Self-citationEllard, S., Flanagan, S. E., Girard, C. A., Patch, A.-M., Harries, L. W., Parrish, A., Edghill, E. L., Mackay, D. J. G., Proks, P., Shimomura, K., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519174 · Cited by 215 · see citing works
Self-citationGribble, F. M., Tucker, S. J., & Ashcroft, F. M. (1997) · The Journal of Physiology · doi:10.1111/j.1469-7793.1997.00035.x · Cited by 161 · see citing works
Self-citationMiki, T., Nagashima, K., & Seino, S. (1999) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0220113 · Cited by 147 · see citing works
Sulfonylurea and K+-Channel Opener Sensitivity of KATP Channels
Koster, J. C., Sha, Q., & Nichols, C. G. (1999) · The Journal of General Physiology · doi:10.1085/jgp.114.2.203 · Cited by 97 · see citing works
“2 subunit (Gribble et al., 1997a).”
InfluentialBabenko, A. P., Gonzalez, G., & Bryan, J. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01215-6 · Cited by 63 · see citing works
- Authors
- Gribble, F. M., Tucker, S. J., & Ashcroft, F. M.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Ashcroft, Frances M.
- ORCID
- Gribble, Fiona M.
- Venue
- The EMBO Journal
- Published
- 1997-03-15
- Volume
- 16
- Issue
- 6
- Pages
- 1145-1152
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1169713
- OpenAlex
- W2103806994
- Cited by
- 341
- References
- 0
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 5 · 2017: 12 · 2016: 8 · 2015: 9 · 2014: 6 · 2013: 12 · 2012: 8
- FWCI
- 12.94
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- SUR1, Walker A motif, ATP-sensitive potassium channels, diazoxide, nucleotide-binding domain, Kir6.2, sulfonylurea receptor, insulin secretion, pancreatic beta cells, nucleotide hydrolysis, channel activation, lysine mutations, magnesium ions
- MeSH terms
- Insulin Secretion, Adenosine Diphosphate, Adenosine Monophosphate, Adenosine Triphosphate, Animals, Antimetabolites, Azides, Cloning, Molecular, Diazoxide, Female, Insulin, Islets of Langerhans, Kinetics, Magnesium, Oocytes, Protein Conformation, Xenopus, Potassium Channels, Mutagenesis, Site-Directed, Sodium Azide, Mice, Rats, In Vitro Techniques
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