A Transmembrane Domain of the Sulfonylurea Receptor Mediates Activation of ATP-Sensitive K+ Channels by K+Channel Openers

  1. Nathalie D’hahan,
  2. Hélène Jacquet,
  3. Christophe Moreau,
  4. Patrice Catty and
  5. Michel Vivaudou
  1. Laboratoire de Biophysique Moleculaire et Celluraire, Département de Biologie Moléculaire et Structurale, Commissariat à l’Energie Atomique, Grenoble, France

    Abstract

    ATP-sensitive K+ (KATP) channels are a complex of an ATP-binding cassette transporter, the sulfonylurea receptor (SUR), and an inward rectifier K+ channel subunit, Kir6.2. The diverse pharmacological responsiveness of KATPchannels from various tissues are thought to arise from distinct SUR isoforms. Thus, when assembled with Kir6.2, the pancreatic β cell isoform SUR1 is activated by the hyperglycemic drug diazoxide but not by hypotensive drugs like cromakalim, whereas the cardiac muscle isoform SUR2A is activated by cromakalim and not by diazoxide. We exploited these differences between SUR1 and SUR2A to pursue a chimeric approach designed to identify the structural determinants of SUR involved in the pharmacological activation of KATPchannels. Wild-type and chimeric SUR were coexpressed with Kir6.2 inXenopus oocytes, and we studied the resulting channels with the patch-clamp technique in the excised inside-out configuration. The third transmembrane domain of SUR is found to be an important determinant of the response to cromakalim, which possibly harbors at least part of its binding site. Contrary to expectations, diazoxide sensitivity could not be linked specifically to the carboxyl-terminal end (nucleotide-binding domain 2) of SUR but appeared to involve complex allosteric interactions between transmembrane and nucleotide-binding domains. In addition to providing direct evidence for the structure-function relationship governing KATPchannel activation by potassium channel-opening drugs, a family of drugs of the highest therapeutic interest, these findings delineate the determinants of ligand specificity within the modular ATP-binding cassette-transporter architecture of SUR.

    Footnotes

    • Send reprint requests to: Dr. Michel Vivaudou, Commissariatà l’Energie Atomique, Département de Biologie Moléculaire et Structurale, Biophysique Moleculaire et Celluraire, 17 rue des Martyrs, 38054, Grenoble, France. E-mail:vivaudou{at}cea.fr

    • This work was supported by grants from Association Francaise contre les Myopathies and Association Francaise de Lutte contre la Mucoviscidose. Additional support was provided by Commissariat àl’Energie Atomique and Centre National de la Recherche Scientifique. N.D., H.J., and C.M. were supported by a fellowship from La Société des Amis des Sciences, a studentship from Association pour la Recherche contre le Cancer, and a studentship from La Ligue contre le Cancer, respectively. A preliminary account of this work has been published in abstract form [Jacquet H, D’hahan N, Moreau C and Vivaudou M (1999) A transmembrane domain of the sulfonylurea receptor mediates activation of K-ATP channels by K-channel-openers. Biophys J76:A413].

    • Abbreviations:
      SUR
      sulfonylurea receptor
      KCO
      potassium channel opener
      KATP channel
      ATP-sensitive potassium channel
      TMD
      transmembrane domain
      NBD
      nucleotide-binding domain
      DMSO
      dimethyl sulfoxide
      PCR
      polymerase chain reaction
      ABC
      ATP-binding cassette
      • Received February 4, 1999.
      • Accepted May 2, 1999.
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    1. Molecular Pharmacology August 1, 1999 vol. 56 no. 2 308-315
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