Molecular Analysis of ATP-sensitive K Channel Gating and Implications for Channel Inhibition by ATP
Open accessAbstract
The β cell KATP channel is an octameric complex of four pore-forming subunits (Kir6.2) and four regulatory subunits (SUR1). A truncated isoform of Kir6.2 (Kir6.2ΔC26), which expresses independently of SUR1, shows intrinsic ATP sensitivity, suggesting that this subunit is primarily responsible for mediating ATP inhibition. We show here that mutation of C166, which lies at the cytosolic end of the second transmembrane domain, to serine (C166S) increases the open probability of Kir6.2ΔC26 approximately sevenfold by reducing the time the channel spends in a long closed state. Rundown of channel activity is also decreased. Kir6.2ΔC26 containing the C166S mutation shows a markedly reduced ATP sensitivity: the Ki is reduced from 175 μM to 2.8 mM. Substitution of threonine, alanine, methionine, or phenylalanine at position C166 also reduced the channel sensitivity to ATP and simultaneously increased the open probability. Thus, ATP does not act as an open channel blocker. The inhibitory effects of tolbutamide are reduced in channels composed of SUR1 and Kir6.2 carrying the C166S mutation. Our results are consistent with the idea that C166 plays a role in the intrinsic gating of the channel, possibly by influencing a gate located at the intracellular end of the pore. Kinetic analysis suggests that the apparent decrease in ATP sensitivity, and the changes in other properties, observed when C166 is mutated is largely a consequence of the impaired transition from the open to the long closed state.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ATP decreases the duration of KATP channel openings and increases the lifetimes of long closed states, whereas MgADP increases burst duration and reduces interburst intervals.
“ATP acts by decreasing the duration of the channel openings and increasing the lifetimes of the long closed states (132, 173, 691). Conversely, MgADP increases burst duration and reduces the interburst intervals (328).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [691]
The Results (Single-Channel Current Analysis; page unavailable) report that ATP shortened channel open time. The Discussion (Effect of Mutations on Channel ATP Sensitivity; page unavailable) says ATP increased the frequency of long closed states but reduced their lifetime in the C166S mutant—the opposite of the claimed lifetime increase. The MgADP clause has a separate citation and is not attributed to this source. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Association and Stoichiometry of KATP Channel Subunits
Clement, J. P., Kunjilwar, K., Gonzalez, G., Schwanstecher, M., Panten, U., Aguilar-Bryan, L., & Bryan, J. (1997) · Neuron · doi:10.1016/s0896-6273(00)80321-9 · Cited by 692 · see citing works
Flagged first, then by citations
Research works printed but not linked: 34
- Aguilar-Bryan L Nichols CG Wechsler SW Clement JP IV Boyd AE González G Herrera-Sosa H Nguy K Bryan J Nelson DA Cloning of the β-cell high-affinity sulphonylurea receptor: a regulator of insulin secretion Science 1995 268 423 425 7716547
- Ashcroft FM Ashcroft SJH Harrison DE Properties of single potassium channels modulated by glucose in rat pancreatic β-cells J Physiol (Camb) 1988 400 501 527 2458459 PMC1191821
- Clement JP IV Kunjilwar K González G Schwanstecher M Panten U Aguilar-Bryan L Bryan J Association and stoichiometry of KATPchannel subunits Neuron 1997 18 827 838 9182806
- Dunne MJ Phosphorylation is required for diazoxide to open ATP-sensitive potassium channels in insulin-secreting cells FEBS Lett 1989 250 262 266 2666156
- Findlay I Dunne MJ ATP maintains ATP-inhibited K+channels in an operational state Pflügers Arch 1986 407 238 240 2428009
- Gillis KD Gee WM Hammoud A McDaniel ML Fahlke LC Misler S Effects of sulphonamides on a metabolite regulated ATP-sensitive K+channel in rat pancreatic β-cells Am J Physiol 1989 257 C1119 C1127 2514595
- Gribble FM Tucker SJ Ashcroft FM The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by MgADP and diazoxide EMBO (Eur Mol Biol Organ) J 1997a 16 1145 1152 9135131 PMC1169713
- Gribble FM Ashfield R Ämmälä C Ashcroft FM Properties of cloned ATP-sensitive K-currents expressed in Xenopusoocytes J Physiol (Camb) 1997b 498 87 98 9023770 PMC1159236
- Gribble FM Tucker SJ Haug T Ashcroft FM MgATP activates the β-cell KATPchannel by interaction with its SUR1 subunit Proc Natl Acad Sci USA 1998 95 7185 7190 9618560 PMC22779
- Holmgren M Smith PL Yellen G Trapping of organic blockers by closing of voltage-dependent K+channels: evidence for a trap door mechanism of activation gating J Gen Physiol 1997 109 527 535 9154902 PMC2217058
- Inagaki N Gonoi T Clement JP IV Namba N Inazawa J Gonzalez G Aguilar-Bryan L Seino S Bryan J Reconstitution of IKATP: an inward rectifier subunit plus the sulphonylurea receptor Science 1995 270 1166 1169 7502040
- Inagaki N Gonoi T Clement JP IV Wang CZ Aguilar-Bryan L Bryan J Seino S A family of sulfonylurea receptors determines the properties of ATP-sensitive K+channels Neuron 1996 16 1011 1017 8630239
- Inagaki N Gonoi T Seino S Subunit stoichiometry of the pancreatic β-cell ATP-sensitive K+channel FEBS Lett 1997 409 232 236 9202152
- Jackson MB Wong BC Morris CE Lecar H Christian CN Successive openings of the same acetylcholine receptor channel are correlated in open time Biophys J 1983 42 109 114 6301575 PMC1329209
- Kakei M Noma A Shibasaki T Properties of adenosine-triphosphate-regulated potassium channels in guinea-pig ventricular cells J Physiol (Camb) 1985 363 441 462 2410608 PMC1192940
- Kozlowski RJ Hales CN Ashford MLJ Dual effects of diazoxide on ATP-K+currents recorded from an insulin- secreting cell line Br J Pharmacol 1989 97 1039 1050 2676059 PMC1854642
- Kyte J Doolittle RF A simple method for displaying the hydropathic character of a protein J Mol Biol 1982 157 105 132 7108955
- Liu Y Holmgren M Jurman ME Yellen G Gated access to the pore of a voltage-dependent K+channel Neuron 1997 19 175 184 9247273
- Lopatin AN Makhina EN Nichols CG Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification Nature 1994 372 366 369 7969496
- Loukin SH Vaillant B Zhou X-L Spalding EP Kung G Saimi Y Random mutagenesis reveals a region important for gating of the yeast K+channel Ykc1 EMBO (Eur Mol Biol Organ) J 1997 16 4817 4825 9305624 PMC1170117
- Nichols CG Lederer WJ Cannell MB ATP-dependence of KATPchannel kinetics in isolated membrane patches from rat ventricle Biophys J 1991 60 1164 1177 1760506 PMC1260172
- Nichols CG Shyng S-L Nestorowicz A Glaser B Clement JP IV Gonzalez G Aguilar-Bryan L Permutt MA Bryan J Adenosine diphosphate as an intracellular regulator of insulin secretion Science 1996 272 1785 1787 8650576
- Ohno-Shosaku T Zünckler B Trube G Dual effects of ATP on K+currents of mouse pancreatic β-cells Pflügers Arch 1987 408 133 138 2436138
- Proks P Ashcroft FM Phentolamine block of KATP channels is mediated by Kir6.2 Proc Natl Acad Sci USA 1997 94 11716 11720 9326676 PMC23609
- Sakura H Ämmälä C Smith PA Gribble FM Ashcroft FM Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel expressed in pancreatic β-cells, brain, heart and skeletal muscle FEBS Lett 1995 377 338 344 8549751
- Shyng SL Ferrigni T Nichols CG Regulation of KATPchannel activity by diazoxide and MgADP: distinct functions of the two nucleotide binding folds of the sulphonylurea receptor J Gen Physiol 1997a 110 643 654 9382893 PMC2229399
- Shyng SL Ferrigni T Nichols CG Control of rectification and gating of KATPchannels by the Kir6.2 subunit J Gen Physiol 1997b 110 141 153 9236207 PMC2233786
- Shyng SL Nichols CG Octameric stoichiometry of the KATPchannel complex J Gen Physiol 1997 110 655 664 9382894 PMC2229396
- Trapp S Tucker SJ Ashcroft FM Activation and inhibition of KATPcurrents by guanine nucleotides is mediated by different channel subunits Proc Natl Acad Sci USA 1997 94 8872 8877 9238070 PMC23175
- Trapp S Tucker SJ Ashcroft FM Mechanism of ATP-sensitive K channel inhibition by sulfhydryl modification J Gen Physiol 1998 112 325 332 9725892 PMC2229416
- Tucker SJ Gribble FM Zhao C Trapp S Ashcroft FM Truncation of Kir6.2 produces ATP-sensitive K-channels in the absence of the sulphonylurea receptor Nature 1997 387 179 183 9144288
- Tucker SJ Gribble FM Proks P Trapp S Ryder TG Haug T Reimann F Ashcroft FM Molecular determinants of KATPchannel inhibition by ATP EMBO (Eur Mol Biol Organ) J 1998 17 3290 3296 9628866 PMC1170667
- Zilberter Y Burnashev N Papin A Portnov V Khodorov B Gating kinetics of ATP-sensitive single potassium channels in myocardial cells depends on electromotive force Pflügers Arch 1988 411 584 589 2455272
- Zong X Zucker H Hofmann F Biel M Three amino acids in the C-linker are major determinants of gating in cyclic nucleotide-gated channels EMBO (Eur Mol Biol Organ) J 1998 17 353 362 9430627 PMC1170386
Cited by
Sorted by citations
Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles
Hibino, H., Inanobe, A., Furutani, K., Murakami, S., Findlay, I., & Kurachi, Y. (2010) · Physiological Reviews · doi:10.1152/physrev.00021.2009 · Cited by 1,518 · see citing works
“2 that change intrinsic channel gating may have a secondary effect to reduce ATP sensitivity (145, 157, 158, 719, 785, 792), probably because ATP preferentially binds to the closed channel (8, 157, 720).”
BackgroundInfluentialGloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032922 · Cited by 1,137 · see citing works
Self-citationPancreatic 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-citationATP-sensitive potassium channelopathies: focus on insulin secretion
Ashcroft, F. M. (2005) · Journal of Clinical Investigation · doi:10.1172/jci25495 · Cited by 627 · see citing works
Self-citationMolecular Mechanisms and Clinical Implications of Reversible Protein <i>S</i> -Glutathionylation
Mieyal, J. J., Gallogly, M. M., Qanungo, S., Sabens, E. A., & Shelton, M. D. (2008) · Antioxidants & Redox Signaling · doi:10.1089/ars.2008.2089 · Cited by 523 · see citing works
“One could imagine that, if Grx1 were expressed at high enough levels, it could serve as an antioxidant by supplying reduced cysteines in a manner analogous to N -acetylcysteine or DTT, but it is unlikely that such concentrations could be reproduced in vivo , even within a disease context.”
InfluentialSulfonylurea 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-citationATP-sensitive K+ channels and insulin secretion: their role in health and disease
Ashcroft, F., & Gribble, F. (1999) · Diabetologia · doi:10.1007/s001250051247 · Cited by 435 · see citing works
Self-citationActivating Mutations in Kir6.2 and Neonatal Diabetes
Hattersley, A. T., & Ashcroft, F. M. (2005) · Diabetes · doi:10.2337/diabetes.54.9.2503 · Cited by 413 · see citing works
Self-citationMitochondrial potassium transport: the K+ cycle
Garlid, K. D., & Paucek, P. (2003) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(03)00108-7 · Cited by 365 · see citing works
“ATP bind, but one is sufficient to inhibit, and models consistent with this interpretation have been presented [114,115].”
Molecular diversity and regulation of renal potassium channels.
Hebert, S., Desir, G., Giebisch, G., & Wang, W.-H. (2005) · Physiological Reviews · doi:10.1152/physrev.00051.2003 · Cited by 323 · see citing works
Crystal structure of a Kir3.1‐prokaryotic Kir channel chimera
Nishida, M., Cadene, M., Chait, B., & MacKinnon, R. (2007) · EMBO Journal · doi:10.1038/sj.emboj.7601828 · Cited by 308 · see citing works
“2 and Kir3 channels (Trapp et al, 1998; Sadja et al, 2001; Yi et al, 2001; Cui et al, 2003; Rapedius et al, 2006; Ribalet et al, 2006).”
Merging functional studies with structures of inward-rectifier K+ channels
Bichet, D., Haass, F. A., & Jan, L. (2003) · Nature Reviews Neuroscience · doi:10.1038/nrn1244 · Cited by 267 · see citing works
Flanagan, S. E., Clauin, S., Bellanné‐Chantelot, C., de Lonlay, P., Harries, L. W., Gloyn, A. L., & Ellard, S. (2008) · Human Mutation · doi:10.1002/humu.20838 · Cited by 241 · see citing works
Proks, P., Antcliff, J. F., Lippiat, J. D., Gloyn, A. L., Hattersley, A. T., & Ashcroft, F. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404756101 · Cited by 232 · see citing works
Self-citationInwardly rectifying potassium channels.
Reimann, F., & Ashcroft, F. (1999) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(99)80073-8 · Cited by 246 · see citing works
Self-citationKATPChannels in the Cardiovascular System
Foster, M. N., & Coetzee, W. A. (2015) · Physiological Reviews · doi:10.1152/physrev.00003.2015 · Cited by 222 · see citing works
Functional analysis of a structural model of the ATP‐binding site of the KATP channel Kir6.2 subunit
Antcliff, J. F., Haider, S. M., Proks, P., Sansom, M. S. P., & Ashcroft, F. M. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600487 · Cited by 185 · see citing works
“V relation between 20 and 100mV (Trapp et al, 1998).”
BackgroundMethodInfluentialSelf-citationStructural Determinants of Pip2 Regulation of Inward Rectifier KATP Channels
Shyng, S., Cukras, C. A., Harwood, J., & Nichols, C. (2000) · The Journal of General Physiology · doi:10.1085/jgp.116.5.599 · Cited by 206 · see citing works
“2 channels is labile; point mutations can render the channel very ATP-insensitive (Tucker et al., 1997, 1998; Drain et al., 1998; Trapp et al., 1998; Enkvetchakul et al., 2000; Loussouarn et al., 2000), and any mutation, or manipulation, that increases open state stability reduces the apparent ATP…”
BackgroundBéguin, P., Nagashima, K., Nishimura, M., Gonoi, T., & Seino, S. (1999) · EMBO Journal · doi:10.1093/emboj/18.17.4722 · Cited by 199 · see citing works
“On one hand, the presence of the phosphate group in human SUR1 reduces open probability, which then becomes similar to rodent KATP channels (Trapp et al., 1998), suggesting that the channels in the basal state naturally tend to be in the low Po mode of gating.”
BackgroundRelapsing diabetes can result from moderately activating mutations in KCNJ11
Gloyn, A. L., Reimann, F. M., Girard, C. A. J., Edghill, E. L., Proks, P., Pearson, E. R., Temple, I. K., Mackay, D., Hamilton-Shield, J. P., Freedenberg, D. L., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi086 · Cited by 193 · see citing works
Self-citationThe kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understanding.
Enkvetchakul, D., Loussouarn, G., Makhina, E., Shyng, S., & Nichols, C. G. (2000) · Biophysical Journal · doi:10.1016/s0006-3495(00)76779-8 · Cited by 172 · see citing works
“Trapp et al. (1998) examined ATP sensitivity and gating behavior of multiple mutations at position 166, also showing that altered ATP sensitivity of M2 mutants is in every case associated with a change in Pozero(see Table 2, Fig.”
BackgroundMethodInfluentialMolecular Basis for K ATP Assembly
Schwappach, B., Zerangue, N., Jan, Y. N., & Jan, L. Y. (2000) · Neuron · doi:10.1016/s0896-6273(00)81146-0 · Cited by 157 · see citing works
“2 (Drain et al., 1998; Trapp et al., 1998; Tucker et al., 1998; Koster et al., 1999; Proks et al., 1999; require any specific knowledge about the structure– function aspects of the protein of interest. Additionally, Reimann et al., 1999).”
Molecular basis of protein kinase C-induced activation of ATP-sensitive potassium channels.
Light, P. E., Bladen, C., Winkfein, R., Walsh, M. P., & French, R. J. (2000) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.160068997 · Cited by 163 · see citing works
Gloyn, A. L., Diatloff-Zito, C., Edghill, E. L., Bellanné‐Chantelot, C., Nivot, S., Coutant, R., Ellard, S., Hattersley, A. T., & Robert, J. J. (2006) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201629 · Cited by 157 · see citing works
Electrophysiology of Islet Cells
Drews, G., Krippeit-Drews, P., & Düfer, M. (2010) · Advances in Experimental Medicine and Biology · doi:10.1007/978-90-481-3271-3_7 · Cited by 152 · see citing works
“In addition, different internal blockers of KATP channels (ATP, Na , Ca, Mg) interfere with different transitions in channel open and closed times and thus modulate the characteristic intrinsic bursts of channel openings (Ashcroft 1988; Woll et al. 1989; Trapp et al. 1998).”
BackgroundNucleotides and phospholipids compete for binding to the C terminus of KATP channels
MacGregor, G., Dong, K., Vanoye, C., Tang, L., Giebisch, G., & Hebert, S. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.042688899 · Cited by 131 · see citing works
Liu, G.-X., Hanley, P. J., Ray, J., & Daut, J. (2001) · Circulation Research · doi:10.1161/hh0901.089881 · Cited by 128 · see citing works
Lin, Y.-F., Jan, Y., & Jan, L. (2000) · EMBO Journal · doi:10.1093/emboj/19.5.942 · Cited by 126 · see citing works
ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles
Tinker, A., Aziz, Q., Li, Y., & Specterman, M. (2018) · Comprehensive Physiology · doi:10.1002/j.2040-4603.2018.tb00049.x · Cited by 123 · see citing works
New insights into KATP channel gene mutations and neonatal diabetes mellitus
Pipatpolkai, T., Usher, S., Stansfeld, P. J., & Ashcroft, F. M. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0351-y · Cited by 122 · see citing works
Self-citationThe ligand‐sensitive gate of a potassium channel lies close to the selectivity filter
Proks, P., Antcliff, J. F., & Ashcroft, F. M. (2003) · EMBO Reports · doi:10.1038/sj.embor.embor708 · Cited by 122
“Mutations in the helix-bundle crossing region dramatically increase the burst duration, but do not alter the duration of the long closed times (Trapp et al., 1998).”
InfluentialSelf-citationState-independent Block of BK Channels by an Intracellular Quaternary Ammonium
Wilkens, C. M., & Aldrich, R. W. (2006) · The Journal of General Physiology · doi:10.1085/jgp.200609579 · Cited by 105 · see citing works
A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome
Proks, P., Girard, C. A. J., Haider, S. M., Gloyn, A. L., Hattersley, A. T., Sansom, M. S. P., & Ashcroft, F. M. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400393 · Cited by 103 · see citing works
“Single-channel currents were recorded at 60mV from small inside-out patches, as described previously (Trapp et al, 1998).”
BackgroundMethodSelf-citationATP and Sulfonylurea Sensitivity of Mutant ATP-Sensitive K+ Channels in Neonatal Diabetes
Koster, J. C., Remedi, M. S., Dao, C., & Nichols, C. G. (2005) · Diabetes · doi:10.2337/diabetes.54.9.2645 · Cited by 93 · see citing works
Proks, P., Capener, C. E., Jones, P., & Ashcroft, F. (2001) · The Journal of General Physiology · doi:10.1085/jgp.118.4.341 · Cited by 101 · see citing works
“2 (Trapp et al., 1998; Tucker et al., 1998; Loussouarn et al., 2000).”
BackgroundMethodInfluentialSelf-citationKoster, J., Sha, Q., Shyng, S., & Nichols, C. (1999) · Journal of Physiology · doi:10.1111/j.1469-7793.1999.019ad.x · Cited by 100 · see citing works
“2 in the absence of SUR1 results in channels which actually have a considerably lower Po,max (Trapp et al. 1998; John et al. 1998), we are forced to suggest that expression of Kir6 in the absence of SUR has an additional effect that results in the lowering of Po to much lower values (•0·1), by an effect besides that o…”
BackgroundInfluentialInvolvement of the N‐terminus of Kir6.2 in coupling to the sulphonylurea receptor
Reimann, F., Tucker, S., Proks, P., & Ashcroft, F. (1999) · Journal of Physiology · doi:10.1111/j.1469-7793.1999.0325p.x · Cited by 97 · see citing works
“It has been shown that mutations which increase Pï also increase the Ké for ATP inhibition (Shyng et al. 1997a; Trapp et al. 1998).”
BackgroundInfluentialSelf-citationLu, T., Hoshi, T., Weintraub, N. L., Spector, A., & Lee, H.-C. (2001) · Journal of Physiology · doi:10.1111/j.1469-7793.2001.00811.x · Cited by 94
“This finding is generally consistent with previous reports (Nichols et al. 1991; Alekseev et al. 1998; Trapp et al. 1998; Enkvetchaul et al. 2000).”
BackgroundResultInfluentialThe Polyamine Binding Site in Inward Rectifier K+ Channels
Kurata, H., Marton, L., & Nichols, C. (2006) · The Journal of General Physiology · doi:10.1085/jgp.200509467 · Cited by 93
Identification of residues contributing to the ATP binding site of Kir6.2
Trapp, S., Haider, S. M., Jones, P. C., Sansom, M. S. P., & Ashcroft, F. M. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg282 · Cited by 77 · see citing works
Self-citationPhosphoinositides Decrease Atp Sensitivity of the Cardiac Atp-Sensitive K+ Channel
Fan, Z., & Makielski, J. (1999) · The Journal of General Physiology · doi:10.1085/jgp.114.2.251 · Cited by 90 · see citing works
“In the presence of Mg21, the potency of ATP inhibition of KATP is partially reduced, an effect attributed to MgATP stimulation of KATP through interaction with the SUR subunit (Gribble et al., 1998).”
Localization of PIP2 activation gate in inward rectifier K+ channels
Xiao, J., Zhen, X.-G., & Yang, J. (2003) · Nature Neuroscience · doi:10.1038/nn1090 · Cited by 89
Gating Mechanism of KATP Channels
Enkvetchakul, D., & Nichols, C. G. (2003) · The Journal of General Physiology · doi:10.1085/jgp.200308878 · Cited by 92 · see citing works
Differential nucleotide regulation of K channels by SUR1 and SUR2A
Masia, R., Enkvetchakul, D., & Nichols, C. G. (2005) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2005.03.009 · Cited by 80 · see citing works
KATP channels gated by intracellular nucleotides and phospholipids.
Baukrowitz, T., & Fakler, B. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01672.x · Cited by 80 · see citing works
“ATP is thought to bind to a closed state and by stabilizing this state to cause inhibition of KATP [20,32,33].”
BackgroundATP‐sensitive potassium channels in capillaries isolated from guinea‐pig heart
Schnitzler, M., Derst, C., Daut, J., & Preisig-müller, R. (2000) · Journal of Physiology · doi:10.1111/j.1469-7793.2000.t01-1-00307.x · Cited by 78 · see citing works
“The channels are characterized by the dependence of their open-state probability on the concentrations of intracellular ATP, ADP and other nucleotides (Yamada et al. 1997; Trapp et al. 1998; Gribble et al. 1998).”
BackgroundFocus on Kir6.2: a key component of the ATP-sensitive potassium channel
Haider, S. M., Antcliff, J. F., Proks, P., Sansom, M. S. P., & Ashcroft, F. M. (2005) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2005.01.007 · Cited by 64 · see citing works
Self-citationIdentification of the PIP2‐binding site on Kir6.2 by molecular modelling and functional analysis
Haider, S., Tarasov, A., Craig, T. J., Sansom, M., & Ashcroft, F. (2007) · EMBO Journal · doi:10.1038/sj.emboj.7601809 · Cited by 75 · see citing works
“…will indirectly reduce inhibition by both sulphonylureas and ATP, as these ligands stabilise the long closed state of the channel, which is entered less frequently (Trapp et al, 1998; Enkvetchakul et al, The EMBO Journal VOL 26 | NO 16 | 2007 &2007 European Molecular Biology Organization3756 2000).”
BackgroundMethodInfluentialSelf-citationFunctional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP
Proks, P., Girard, C. A. J., & Ashcroft, F. M. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi305 · Cited by 74 · see citing works
“An alternative idea is that the pedestal arises from an impaired efficacy of channel closure, as observed previously for the C166S and L164C mutations in Kir6.2DC channels ( 38 ,39).”
BackgroundSelf-citationBabenko, A. P., González, G., & Bryan, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.11587 · Cited by 75 · see citing works
Babenko, A. P., Gonzalez, G., & Bryan, J. (1999) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1006/bbrc.1999.0172 · Cited by 74 · see citing works
Involvement of the N‐terminus of Kir6.2 in the inhibition of the KATP channel by ATP
Proks, P., Gribble, F., Adhikari, R., Tucker, S., & Ashcroft, F. M. (1999) · Journal of Physiology · doi:10.1111/j.1469-7793.1999.019af.x · Cited by 74 · see citing works
Self-citationMolecular structure of an open human KATP channel
Zhao, C., & MacKinnon, R. (2021) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2112267118 · Cited by 72 · see citing works
Modeling KATP channel gating and its regulation
Proks, P., & Ashcroft, F. M. (2008) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2008.10.002 · Cited by 65 · see citing works
Self-citationKrauter, T., Ruppersberg, J., & Baukrowitz, T. (2001) · Molecular Pharmacology · doi:10.1124/mol.59.5.1086 · Cited by 70 · see citing works
“2 that are possibly involved in the binding of ATP (Tucker et al., 1997; Drain et al., 1998; Trapp et al., 1998).”
BackgroundRafiq, M., Flanagan, S. E., Patch, A., Shields, B. M., Ellard, S., Hattersley, A. T., & The Neonatal Diabetes International Collaborative Group (2008) · Diabetes Care · doi:10.2337/dc07-1785 · Cited by 265 · see citing works
“This can be explained by in vitro studies that found that mutations associated with neurological symptoms are less responsive to sulfonylureas as well as responding less to ATP (19,20).”
InfluentialHyperinsulinemic Hypoglycemia – The Molecular Mechanisms
Nessa, A., Rahman, S. A., & Hussain, K. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00029 · Cited by 66 · see citing works
How ATP Inhibits the Open KATP Channel
Craig, T. J., Ashcroft, F. M., & Proks, P. (2008) · The Journal of General Physiology · doi:10.1085/jgp.200709874 · Cited by 67 · see citing works
“Previous single-channel studies have characterized the ATP dependence of the mean open time and the mean burst duration ( Davies et al., 1992 ; Trapp et al., 1998 ; Fan and Makielski, 1999 ; Li et al., 2002 ).”
BackgroundMethodInfluentialSelf-citationKir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2–SUR1 interactions
Tammaro, P., Girard, C. A. J., Molnes, J., Njølstad, P. R., & Ashcroft, F. M. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600715 · Cited by 62 · see citing works
“Single-channel currents were recorded at 60mV from small inside-out patches, low-pass filtered at 5 kHz and sampled at 20–50 kHz (Trapp et al, 1998).”
BackgroundMethodSelf-citationStructural and functional analysis of the putative pH sensor in the Kir1.1 (ROMK) potassium channel
Rapedius, M., Haider, S., Browne, K. F., Shang, L., Sansom, M. S. P., Baukrowitz, T., & Tucker, S. (2006) · EMBO Reports · doi:10.1038/sj.embor.7400678 · Cited by 64
“But in both cases, these effects are explained by changes in their intrinsic gating properties, rather than by loss of ligand binding (Trapp et al, 1998; Yi et al, 2001; Wang et al, 2005).”
BackgroundSelf-citationBabenko, A. P., Gonzalez, G., & Bryan, J. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01215-6 · Cited by 63 · see citing works
Gating and Inward Rectifying Properties of the MthK K+ Channel with and without the Gating Ring
Li, Y., Berke, I., Chen, L.-P., & Jiang, Y.-X. (2007) · The Journal of General Physiology · doi:10.1085/jgp.200609655 · Cited by 62
Noble Gas Xenon Is a Novel Adenosine Triphosphate-sensitive Potassium Channel Opener
Bantel, C., Maze, M., & Trapp, S. (2010) · Anesthesiology · doi:10.1097/aln.0b013e3181cf894a · Cited by 61 · see citing works
“This mutant was chosen because it not only disrupts ATP inhibition but also leaves the intrinsic open probability of the channel virtually unchanged, thus excluding changes in ligand sensitivity secondary to intrinsic gating.(19,20) When coexpressed with SUR1, this channel exhibited large whole cell currents, but addi…”
BackgroundSelf-citationFunctional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes
Girard, C. A. J., Shimomura, K., Proks, P., Absalom, N. L., Castaño, L. A., de Nanclares, G. P., & Ashcroft, F. M. (2006) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-006-0112-3 · Cited by 60 · see citing works
Self-citationShimomura, K., Girard, C. A. J., Proks, P., Nazim, J., Lippiat, J. D., Cerutti, F., Lorini, R., Ellard, S., Hattersley, A. T., Barbetti, F., et al. (2006) · Diabetes · doi:10.2337/db05-1640 · Cited by 62 · see citing works
Self-citationTsuboi, T., Lippiat, J. D., Ashcroft, F. M., & Rutter, G. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0306347101 · Cited by 50 · see citing works
Self-citationATP Interaction with the Open State of the KATP Channel
Enkvetchakul, D., Loussouarn, G., Makhina, E., & Nichols, C. G. (2001) · Biophysical Journal · doi:10.1016/s0006-3495(01)76051-1 · Cited by 56 · see citing works
Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome
Proks, P., Shimomura, K., Craig, T. J., Girard, C. A. J., & Ashcroft, F. M. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm149 · Cited by 52 · see citing works
Self-citationXu, H.-X., Wu, J., Cui, N., Abdulkadir, L., Wang, R.-P., Mao, J., Giwa, L. R., Chanchevalap, S., & Jiang, C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106595200 · Cited by 54
The Carboxyl Termini of KATP Channels Bind Nucleotides
Vanoye, C. G., MacGregor, G. G., Dong, K., Tang, L., Buschmann, A. S., Hall, A. E., Lu, M. W., Giebisch, G., & Hébert, S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112004200 · Cited by 55 · see citing works
Molecular basis for Kir6.2 channel inhibition by adenine nucleotides.
Ribalet, B., John, S., & Weiss, J. (2003) · Biophysical Journal · doi:10.1016/s0006-3495(03)74847-4 · Cited by 53 · see citing works
“…KATP channels by adenine nucleotides To account for the increased ATP binding affinity associated with decreased Po, it has been suggested that channel inhibition by ATP involves preferential binding of ATP to a closed state (Trapp et al., 1998; Fan and Makielski, 1999; Enkvetchakul et al., 2000).”
BackgroundInfluentialReimann, F., Ryder, T., Tucker, S. J., & Ashcroft, F. M. (1999) · Journal of Physiology · doi:10.1111/j.1469-7793.1999.00661.x · Cited by 52 · see citing works
“One mechanism by which a mutation may indirectly alter the channel ATP sensitivity is by impairing the ability of the channel to close (Shyng et al. 1997a; Trapp et al. 1998).”
BackgroundSelf-citationActivation of the KATP channel by Mg-nucleotide interaction with SUR1
Proks, P., de Wet, H., & Ashcroft, F. M. (2010) · Journal of General Physiology · doi:10.1085/jgp.201010475 · Cited by 51 · see citing works
“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-citationHao, M., & Bogan, J. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.038034 · Cited by 61 · see citing works
Casamassima, M., D'Adamo, M., Pessia, M., & Tucker, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306596200 · Cited by 51 · see citing works
Self-citationMolecular Basis and Structural Insight of Vascular KATP Channel Gating by S-Glutathionylation*
Yang, Y., Shi, W., Chen, X., Cui, N., Konduru, A. S., Shi, Y., Trower, T. C., Zhang, S., & Jiang, C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.195123 · Cited by 50
Li, L., Wang, J., & Drain, P. (2000) · Biophysical Journal · doi:10.1016/s0006-3495(00)76340-5 · Cited by 50
“…closings, and these active burst episodes are separated by long-lived inactive interburst intervals (Alekseev et al., 1997; Ashcroft et al., 1984; Babenko et al., 1999a,b; Cook and Hales, 1984; Drain et al., 1998; Gillis et al., 1989; Nichols et al., 1991; Qin et al., 1989; Trapp et al., 1998).”
BackgroundInfluentialAltered functional properties of KATP channel conferred by a novel splice variant of SUR1
Sakura, H., Trapp, S., Liss, B., & Ashcroft, F. M. (1999) · Journal of Physiology · doi:10.1111/j.1469-7793.1999.00337.x · Cited by 49 · see citing works
Self-citationBabenko, A. P., González, G., Aguilar-Bryan, L., & Bryan, J. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)00102-7 · Cited by 49 · see citing works
Kawano, T., Oshita, S., Takahashi, A., Tsutsumi, Y., Tomiyama, Y., Kitahata, H., Kuroda, Y., & Nakaya, Y. (2004) · Anesthesiology · doi:10.1097/00000542-200408000-00020 · Cited by 46
“0 channel lines the intracellular mouth of the pore, because mutations within this region affect the channel gating kinetics.(23,25) The residues at cytosolic end of the second transmembrane domain of Kir6.”
BackgroundKawano, T., Oshita, S., Takahashi, A., Tsutsumi, Y., Tomiyama, Y., Kitahata, H., Kuroda, Y., & Nakaya, Y. (2004) · Anesthesiology · doi:10.1097/00000542-200402000-00024 · Cited by 46
“2 lesions, namely, the R50D lesion in the N-terminus and a lesion in the C-terminus that includes C166S, T171A, K185Q, and G334D.(26,27) We confirmed these observations (fig.”
Permeant Ion-Dependent Changes in Gating of Kir2.1 Inward Rectifier Potassium Channels
Lu, T., Wu, L., Xiao, J., & Yang, J. (2001) · The Journal of General Physiology · doi:10.1085/jgp.118.5.509 · Cited by 46
“In cloned G protein-coupled or ATPsensitive Kir channels, single-channel gating is characterized by bursts of rapid openings (millisecond time scale) separated by long closed intervals (Trapp et al., 1998; Enkvetchakul et al., 2000; Yakubovich et al., 2000).”
BackgroundMechanism of ATP-sensitive K Channel Inhibition by Sulfhydryl Modification
Trapp, S., Tucker, S., & Ashcroft, F. (1998) · The Journal of General Physiology · doi:10.1085/jgp.112.3.325 · Cited by 44 · see citing works
“2DC26-166S currents argues that the thiol reagent may not block the open state of the channel, which is markedly increased in frequency by the C166S mutation (Trapp et al., 1998).”
BackgroundInfluentialSelf-citationCryo-electron microscopy structures and progress toward a dynamic understanding of KATP channels
Puljung, M. C. (2018) · The Journal of General Physiology · doi:10.1085/jgp.201711978 · Cited by 42 · see citing works
“, 1998) or increase the intrinsic Po (e.g., Kir6.2-C166S; Trapp et al., 1998) may prove necessary if an open-state structure is to be obtained.”
BackgroundRibalet, B., John, S., & Weiss, J. (2000) · The Journal of General Physiology · doi:10.1085/jgp.116.3.391 · Cited by 42 · see citing works
“2, which involve two distinct regions of the pore-forming protein (Drain et al., 1998; Tucker et al., 1998).”
BackgroundMembrane Ion Channels and Diabetes
Proks, P., & Lippiat, J. D. (2006) · Current Pharmaceutical Design · doi:10.2174/138161206775474431 · Cited by 41 · see citing works
Self-citationGarcin, L., Mericq, V., Fauret-Amsellem, A.-L., Cavé, H., Polak, M., & Beltrand, J. (2020) · Pediatric Diabetes · doi:10.1111/pedi.13041 · Cited by 39 · see citing works
Schroeder, I., & Hansen, U. (2007) · The Journal of General Physiology · doi:10.1085/jgp.200709802 · Cited by 39 · see citing works
Allosteric modulation of the mouse kir6.2 channel by intracellular H+ and ATP
Wu, J.-P., Cui, N., Piao, H., Wang, Y., Xu, H.-X., Mao, J., & Jiang, C. (2002) · Journal of Physiology · doi:10.1113/jphysiol.2002.025247 · Cited by 38 · see citing works
“2 channel (Shyng et al. 1997a; Drain et al. 1998; Trapp et al. 1998; Tucker et al. 1998; Koster et al. 1999; Proks et al. 1999b; Reimann et al. 1999).”
Li, L., Geng, X.-H., & Drain, P. (2002) · The Journal of General Physiology · doi:10.1085/jgp.119.1.105 · Cited by 37 · see citing works
“A second inhibitory action is ATP binding to the active open state (Ashcroft et al., 1988; Drain et al., 1998; Ashcroft and Kakei, 1989; Fan and Makielski, 1999; Gillis et al., 1989; Nichols et al., 1991; Trapp et al., 1998).”
BackgroundATP-Sensitive Potassium Channels in Health and Disease
Clark, R. H., & Proks, P. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-90-481-3271-3_8 · Cited by 29 · see citing works
“nucleotides (Trapp et al. 1998).”
Self-citationProks, P., Girard, C. A. J., Bævre, H., Njølstad, P. R., & Ashcroft, F. M. (2006) · Diabetes · doi:10.2337/db05-1420 · Cited by 40 · see citing works
Self-citationTammaro, P., Proks, P., & Ashcroft, F. M. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.099168 · Cited by 35 · see citing works
“Previous studies have shown that mutations which stabilize the intrinsic open state of the channel (Po(0)) result in a reduced sensitivity to ATP (Trapp et al. 1998; Enkvetchakul et al. 2000; Proks et al. 2004; see also Fig.”
BackgroundSelf-citationYang, H.-Q., Martinez-Ortiz, W., Hwang, J., Fan, X., Cardozo, T., & Coetzee, W. (2020) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1918088117 · Cited by 34 · see citing works
Requirement of Multiple Protein Domains and Residues for GatingK ATP Channels by Intracellular pH*
Piao, H., Cui, N., Xu, H.-X., Mao, J., Rojas, A., Wang, R.-P., Abdulkadir, L., Li, L., Wu, J.-P., & Jiang, C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106123200 · Cited by 34
Mechanistic insights on KATP channel regulation from cryo-EM structures
Driggers, C., & Shyng, S. (2022) · The Journal of General Physiology · doi:10.1085/jgp.202113046 · Cited by 47 · see citing works
“Both poses are consistent with previous functional data implicating R50 and N335 in ATP binding (Drain et al., 1998; John et al., 2003; Trapp et al., 1998).”
Regulation of the ATP-sensitive K channel Kir6.2 by ATP and PIP(2).
Ribalet, B., John, S., Xie, L.-H., & Weiss, J. (2005) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2004.11.018 · Cited by 33 · see citing works
Concerted Gating Mechanism Underlying KATP Channel Inhibition by ATP
Drain, P. F., Geng, X., & Li, L. (2004) · Biophysical Journal · doi:10.1016/s0006-3495(04)74269-1 · Cited by 35 · see citing works
“2, with residues of the cytoplasmic N-terminus also involved (Tucker et al., 1997, 1998; Drain et al., 1998; Takano et al., 1998; Trapp et al., 1998; Koster et al., 1999; Babenko et al., 1999c; Proks et al., 1999; Reimann et al., 1999; Tanabe et al., 1999, 2000; Li et al., 2000; MacGregor et al., 2002; Vanoye et al.,…”
BackgroundInfluentialAmani, R., Borcik, C. G., Khan, N. H., Versteeg, D. B., Yekefallah, M., Do, H. Q., Coats, H. R., & Wylie, B. J. (2020) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1915010117 · Cited by 31
Gönen, M. S., Arıkoğlu, H., Kaya, D. E., Özdemir, H., İpekçi, S. H., Arslan, A., Kayış, S. A., & Göğebakan, B. (2012) · Archives of Medical Research · doi:10.1016/j.arcmed.2012.06.001 · Cited by 40 · see citing works
- Authors
- Trapp, S., Proks, P., Tucker, S. J., & Ashcroft, F. M.
- Affiliations
- University of Oxford (GB)
- Venue
- The Journal of General Physiology
- Publisher
- Rockefeller University Press
- Published
- 1998-09-01
- Volume
- 112
- Issue
- 3
- Pages
- 333-349
- ISSN
- 0022-1295 (ISSN-L)
- 1540-7748
- PMC
- PMC2229413
- OpenAlex
- W2135200866
- Cited by
- 170
- References
- 35
- Citations by year
- 2026: 1 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 8 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 2 · 2015: 3 · 2014: 6 · 2013: 4 · 2012: 5
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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)
- UCL Discovery (University College London) (submittedVersion)
- 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
- ATP-sensitive potassium channels, Kir6.2, SUR1, channel gating, ATP inhibition, open probability, rundown, tolbutamide
- MeSH terms
- Adenosine Triphosphate, Animals, Cysteine, Female, Kinetics, Oocytes, Xenopus laevis, Potassium Channels, Ion Channel Gating, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Potassium Channels, Inwardly Rectifying, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
