Activation of the KATP channel by Mg-nucleotide interaction with SUR1
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The mechanism of adenosine triphosphate (ATP)-sensitive potassium (KATP) channel activation by Mg-nucleotides was studied using a mutation (G334D) in the Kir6.2 subunit of the channel that renders KATP channels insensitive to nucleotide inhibition and has no apparent effect on their gating. KATP channels carrying this mutation (Kir6.2-G334D/SUR1 channels) were activated by MgATP and MgADP with an EC50 of 112 and 8 µM, respectively. This activation was largely suppressed by mutation of the Walker A lysines in the nucleotide-binding domains of SUR1: the remaining small (∼10%), slowly developing component of MgATP activation was fully inhibited by the lipid kinase inhibitor LY294002. The EC50 for activation of Kir6.2-G334D/SUR1 currents by MgADP was lower than that for MgATP, and the time course of activation was faster. The poorly hydrolyzable analogue MgATPγS also activated Kir6.2-G334D/SUR1. AMPPCP both failed to activate Kir6.2-G334D/SUR1 and to prevent its activation by MgATP. Maximal stimulatory concentrations of MgATP (10 mM) and MgADP (1 mM) exerted identical effects on the single-channel kinetics: they dramatically elevated the open probability (PO > 0.8), increased the mean open time and the mean burst duration, reduced the frequency and number of interburst closed states, and eliminated the short burst states. By comparing our results with those obtained for wild-type KATP channels, we conclude that the MgADP sensitivity of the wild-type KATP channel can be described quantitatively by a combination of inhibition at Kir6.2 (measured for wild-type channels in the absence of Mg2+) and activation via SUR1 (determined for Kir6.2-G334D/SUR1 channels). However, this is not the case for the effects of MgATP.
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Coexpressing SUR1 with Kir6.2 carrying a mutation that renders it ATP-insensitive yields EC50 of 8 μM for MgADP and 112 μM for MgATP.
“However, it can be estimated by coexpressing SUR1 with Kir6.2 carrying a mutation that renders it ATP-insensitive. This yields EC50 of 8 µM for MgADP and 112 µM for MgATP (523): it is believed that the lower affinity of MgATP reflects the fact that it must be hydrolyzed to MgADP before it can stimulate channel opening.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [523]
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Association and Stoichiometry of KATP Channel Subunits
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Molecular Analysis of ATP-sensitive K Channel Gating and Implications for Channel Inhibition by ATP
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“It is noteworthy that the properties of maximally activated channels are similar to those of mutant KATP channels with strongly impaired gating (PO(0) 0.8; e.g., Trapp et al., 1998; Enkvetchakul et al., 2001; Proks et al., 2005a, 2007).”
BackgroundInfluentialSelf-citationCoupling of Cell Energetics with Membrane Metabolic Sensing
Abraham, M. R., Selivanov, V. A., Hodgson, D. M., Pucar, D., Zingman, L. V., Wieringa, B., Dzeja, P. P., Alekseev, A. E., & Terzic, A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201777200 · Cited by 148 · see citing works
ATP-sensitive K <sup>+</sup> channels and disease: from molecule to malady
Ashcroft, F. M. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00348.2007 · Cited by 107 · cited 1× · see citing works
“…4 389–405 www.jgp.org/cgi/doi/10.1085/jgp.201010475 389 I N T R O D U C T I O N ATP-sensitive potassium (KATP) channels serve as metabolic sensors, coupling cell metabolism to plasmalemmal potassium fluxes and electrical activity in a variety of cell types (Miki and Seino, 2005; Ashcroft, 2007).”
BackgroundInfluentialSelf-citationMarkworth, E., Schwanstecher, C., & Schwanstecher, M. (2000) · Diabetes · doi:10.2337/diabetes.49.9.1413 · Cited by 76 · see citing works
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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-citation
- Authors
- Proks, P., de Wet, H., & Ashcroft, F. M.
- Affiliations
- University of Oxford (GB)
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, England, UK
- Corresponding author
- Proks, Peter
- Ashcroft, Frances M.
- Venue
- Journal of General Physiology
- Publisher
- Rockefeller University Press
- Published
- 2010-09-27
- Volume
- 136
- Issue
- 4
- Pages
- 389-405
- ISSN
- 0022-1295 (ISSN-L)
- 1540-7748
- PMC
- PMC2947056
- OpenAlex
- W2023645748
- Cited by
- 51
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 2 · 2014: 6 · 2013: 6 · 2012: 1
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of General Physiology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (084655)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- ATP-sensitive potassium channels, SUR1, Kir6.2, MgATP, MgADP, nucleotide-binding domain, LY294002, AMP-PCP, single-channel kinetics, open probability, nucleotide inhibition
- MeSH terms
- Adenosine Diphosphate, Adenosine Triphosphate, Animals, Hydrolysis, Kinetics, Oocytes, Receptors, Drug, Xenopus, Ion Channel Gating, Patch-Clamp Techniques, ATP-Binding Cassette Transporters, Potassium Channels, Inwardly Rectifying, Rats, KATP Channels, Sulfonylurea Receptors
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