MolPharm xPharm- The Comprehensive Pharmacology Reference

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Gribble, F. M.
Right arrow Articles by Ashcroft, F. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gribble, F. M.
Right arrow Articles by Ashcroft, F. M.

Vol. 57, Issue 6, 1256-1261, June 2000

Nucleotide Modulation of Pinacidil Stimulation of the Cloned KATP Channel Kir6.2/SUR2A

Fiona M. Gribble, Frank Reimann, Rebecca Ashfield, and Frances M. Ashcroft

University Laboratory of Physiology, Oxford, United Kingdom

ATP-sensitive K+ channels are the target for K+ channel openers such as pinacidil. These channels are formed from pore-forming Kir6.2 and regulatory sulfonylurea receptor (SUR) subunits. Pinacidil activates channels containing SUR2A (heart, skeletal muscle), but not those containing SUR1 (beta  cells). Surprisingly, binding of the pinacidil analog [3H]P1075 is dependent on added nucleotides, yet in electrophysiological studies, pinacidil is effective in the absence of intracellular nucleotides. To determine the reason for this anomaly, we examined the functional interactions between pinacidil (or P1075) and nucleotides by expressing cloned Kir6.2/SUR2A channels in Xenopus laevis oocytes. Both pinacidil and P1075 activated macroscopic Kir6.2/SUR2A currents in the absence of added nucleotide, but the presence of intracellular ATP or ADP slowed the off-rate of the response. Mutation of the Walker A lysine in a single nucleotide binding domain (NBD) of SUR2A (K707A in NBD1, K1348A in NBD2), abolished this action of nucleotide. The K1348A mutation prevented stimulation by MgADP but had little effect on the amplitude of the pinacidil response. In contrast, Kir6.2/SUR2A-K707A currents were activated by MgADP, but only responded to pinacidil in the presence of Mg-nucleotide. Off-rates in the absence (or presence) of nucleotide were slower for the pinacidil analog P1075 than for pinacidil, consistent with the higher affinity of P1075. We suggest that slowing of P1075 dissociation by nucleotide enables binding to be detected.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Circ. Res.Home page
P. Philip-Couderc, N. I. Tavares, A. Roatti, R. Lerch, C. Montessuit, and A. J. Baertschi
Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism
Circ. Res., February 1, 2008; 102(2): e20 - e35.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
M. Zhou, H.-J. He, R. Suzuki, K.-X. Liu, O. Tanaka, M. Sekiguchi, H. Itoh, K. Kawahara, and H. Abe
Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart
J. Histochem. Cytochem., August 1, 2007; 55(8): 795 - 804.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Cui, Y. Kang, Y. He, Y.-M. Leung, H. Xie, E. A. Pasyk, X. Gao, L. Sheu, J. B. Hansen, P. Wahl, et al.
H3 Domain of Syntaxin 1A Inhibits KATP Channels by Its Actions on the Sulfonylurea Receptor 1 Nucleotide-Binding Folds-1 and -2
J. Biol. Chem., December 17, 2004; 279(51): 53259 - 53265.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
P. S. Fischbach, A. White, T. D. Barrett, and B. R. Lucchesi
Risk of Ventricular Proarrhythmia with Selective Opening of the Myocardial Sarcolemmal versus Mitochondrial ATP-Gated Potassium Channel
J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 554 - 559.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
M. Dabrowski, F. M. Ashcroft, R. Ashfield, P. Lebrun, B. Pirotte, J. Egebjerg, J. Bondo Hansen, and P. Wahl
The Novel Diazoxide Analog 3-Isopropylamino-7-Methoxy-4H-1,2,4-Benzothiadiazine 1,1-Dioxide Is a Selective Kir6.2/SUR1 Channel Opener
Diabetes, June 1, 2002; 51(6): 1896 - 1906.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. V. Zingman, D. M. Hodgson, M. Bienengraeber, A. B. Karger, E. C. Kathmann, A. E. Alekseev, and A. Terzic
Tandem Function of Nucleotide Binding Domains Confers Competence to Sulfonylurea Receptor in Gating ATP-sensitive K+ Channels
J. Biol. Chem., April 12, 2002; 277(16): 14206 - 14210.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
F. Reimann, F. M. Ashcroft, and F. M. Gribble
Structural Basis for the Interference Between Nicorandil and Sulfonylurea Action
Diabetes, October 1, 2001; 50(10): 2253 - 2259.
[Abstract] [Full Text]

Home page
 Mol. Pharmacol.Home page
F. Reimann, F. M. Gribble, and F. M. Ashcroft
Differential Response of KATP Channels Containing SUR2A or SUR2B Subunits to Nucleotides and Pinacidil
Mol. Pharmacol., April 13, 2001; 58(6): 1318 - 1325.
[Abstract] [Full Text]

Home page
 J. Biol. Chem.Home page
M. Matsuo, K. Tanabe, N. Kioka, T. Amachi, and K. Ueda
Different Binding Properties and Affinities for ATP and ADP among Sulfonylurea Receptor Subtypes, SUR1, SUR2A, and SUR2B
J. Biol. Chem., September 8, 2000; 275(37): 28757 - 28763.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D.-K. Song and F. M. Ashcroft
ATP Modulation of ATP-sensitive Potassium Channel ATP Sensitivity Varies with the Type of SUR Subunit
J. Biol. Chem., March 2, 2001; 276(10): 7143 - 7149.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
J. C. Koster, A. Knopp, T. P. Flagg, K. P. Markova, Q. Sha, D. Enkvetchakul, T. Betsuyaku, K. A. Yamada, and C. G. Nichols
Tolerance for ATP-Insensitive KATP Channels in Transgenic Mice
Circ. Res., November 23, 2001; 89(11): 1022 - 1029.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics