HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dabrowski, M. Articles by Wahl, P. Search for Related Content PubMed PubMed Citation Articles by Dabrowski, M. Articles by Wahl, P. Social Bookmarking                What's this?

The Novel Diazoxide Analog 3-Isopropylamino-7-Methoxy-4H-1,2,4-Benzothiadiazine 1,1-Dioxide Is a Selective Kir6.2/SUR1 Channel Opener

¹ Research & Development, Novo Nordisk, Malov, Denmark
² University Laboratory of Physiology, Oxford, U.K
³ Laboratory of Pharmacology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium
⁴ Department of Medicinal Chemistry, Institute of Pharmacy, University of Liege, Liege, Belgium
⁵ Institute of Molecular and Structural Biology, Aarhus University, Aarhus, Denmark

ATP-sensitive K⁺ (K_ATP) channels are activated by a diverse group of compounds known as potassium channel openers (PCOs). Here, we report functional studies of the Kir6.2/SUR1 Selective PCO 3-isopropylamino-7-methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide (NNC 55-9216). We recorded cloned K_ATP channel currents from inside-out patches excised from Xenopus laevis oocytes heterologously expressing Kir6.2/SUR1, Kir6.2/SUR2A, or Kir6.2/SUR2B, corresponding to the ß-cell, cardiac, and smooth muscle types of the K_ATP channel. NNC 55-9216 reversibly activated Kir6.2/SUR1 currents (EC₅₀ = 16 µmol/l). This activation was dependent on intracellular MgATP and was abolished by mutation of a single residue in the Walker A motifs of either nucleotide-binding domain of SUR1. The drug had no effect on Kir6.2/SUR2A or Kir6.2/SUR2B currents. We therefore used chimeras of SUR1 and SUR2A to identify regions of SUR1 involved in the response to NNC 55-9216. Activation was completely abolished and significantly reduced by swapping transmembrane domains 8–11. The reverse chimera consisting of SUR2A with transmembrane domains 8–11 and NBD2 consisting SUR1 was activated by NNC 55-9216, indicating that these SUR1 regions are important for drug activation. [³H]glibenclamide binding to membranes from HEK293 cells transfected with SUR1 was displaced by NNC 55-9216 (IC₅₀ = 105 µmol/l), and this effect was impaired when NBD2 of SUR1 was replaced by that of SUR2A. These results suggest NNC 55-9216 is a SUR1-selective PCO that requires structural determinants, which differ from those needed for activation of the K_ATP channel by pinacidil and cromakalim. The high selectivity of NNC 55-9216 may prove to be useful for studies of the molecular mechanism of PCO action.

CiteULike

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				B. Ng, Y. Kang, C. L. Elias, Y. He, H. Xie, J. B. Hansen, P. Wahl, and H. Y. Gaisano The Actions of a Novel Potent Islet {beta}-Cell Specific ATP-Sensitive K+ Channel Opener Can Be Modulated by Syntaxin-1A Acting on Sulfonylurea Receptor 1 Diabetes, August 1, 2007; 56(8): 2124 - 2134. [Abstract] [Full Text] [PDF]

				B. Raju and P. E. Cryer Mechanism, temporal patterns, and magnitudes of the metabolic responses to the KATP channel agonist diazoxide Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E80 - E85. [Abstract] [Full Text] [PDF]

				J. Bryan, W. H. Vila-Carriles, G. Zhao, A. P. Babenko, and L. Aguilar-Bryan Toward Linking Structure With Function in ATP-Sensitive K+ Channels Diabetes, December 1, 2004; 53(suppl_3): S104 - S112. [Abstract] [Full Text] [PDF]

				A. Hambrock, T. Kayar, D. Stumpp, and H. Osswald Effect of Two Amino Acids in TM17 of Sulfonylurea Receptor SUR1 on the Binding of ATP-Sensitive K+ Channel Modulators Diabetes, December 1, 2004; 53(suppl_3): S128 - S134. [Abstract] [Full Text] [PDF]

				P. Arkhammar, P. Wahl, B. Gerlach, T. Fremming, and J. B. Hansen Establishment and Application of in Vitro Membrane Potential Assays in Cell Lines with Endogenous or Recombinant Expression of ATP-Sensitive Potassium Channels (Kir6.2/SUR1) Using a Fluorescent Probe Kit J Biomol Screen, August 1, 2004; 9(5): 382 - 390. [Abstract] [PDF]

				R. A. Ritzel, J. B. Hansen, J. D. Veldhuis, and P. C. Butler Induction of {beta}-Cell Rest by a Kir6.2/SUR1-Selective KATP-Channel Opener Preserves {beta}-Cell Insulin Stores and Insulin Secretion in Human Islets Cultured at High (11 mM) Glucose J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 795 - 805. [Abstract] [Full Text] [PDF]

				M. J. DUNNE, K. E. COSGROVE, R. M. SHEPHERD, A. AYNSLEY-GREEN, and K. J. LINDLEY Hyperinsulinism in Infancy: From Basic Science to Clinical Disease Physiol Rev, January 1, 2004; 84(1): 239 - 275. [Abstract] [Full Text] [PDF]