ATPase activity of the sulfonylurea receptor: A catalytic function for the K(ATP) channel complex

Martin Bienengraeber, Alexey E. Alekseev, M. Roselle Abraham, Antonio J. Carrasco, Christophe Moreau, Michel Vivaudou, Petras P. Dzeja, Andre Terzic

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

ATP-sensitive K+ (K(ATP)) channels are unique metabolic sensors formed by association of Kir6.2, an inwardly rectifying K+ channel, and the sulfonylurea receptor SUR, an ATP binding cassette protein. We identified an ATPase activity in immunoprecipitates of cardiac K(ATP) channels and in purified fusion proteins containing nucleotide binding domains NBD1 and NBD2 of the cardiac SUR2A isoform. NBD2 hydrolyzed ATP with a twofold higher rate compared to NBD1. The ATPase required Mg2+ and was insensitive to ouabain, oligomycin, thapsigargin, or levamisole. K1348A and D1469N mutations in NBD2 reduced ATPase activity and produced channels with increased sensitivity to ATP. K(ATP) channel openers, which bind to SUR, promoted ATPase activity in purified sarcolemma. At higher concentrations, openers reduced ATPase activity, possibly through stabilization of MgADP at the channel site. K1348A and D1469N mutations attenuated the effect of openers on K(ATP) channel activity. Opener-induced channel activation was also inhibited by the creatine kinase/creatine phosphate system that removes ADP from the channel complex. Thus, the K(ATP) channel complex functions not only as a K+ conductance, but also as an enzyme regulating nucleotide-dependent channel gating through an intrinsic ATPase activity of the SUR subunit. Modulation of the channel ATPase activity and/or scavenging the product of the ATPase reaction provide novel means to regulate cellular functions associated with K(ATP) channel opening.

Original languageEnglish (US)
Pages (from-to)1943-1952
Number of pages10
JournalFASEB Journal
Volume14
Issue number13
StatePublished - Oct 16 2000

Keywords

  • ABC proteins
  • ATP-sensitive K channels
  • Enzyme
  • Kit6.2
  • Nucleotide binding domains
  • Potassium channel openers
  • SUR

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Bienengraeber, M., Alekseev, A. E., Abraham, M. R., Carrasco, A. J., Moreau, C., Vivaudou, M., Dzeja, P. P., & Terzic, A. (2000). ATPase activity of the sulfonylurea receptor: A catalytic function for the K(ATP) channel complex. FASEB Journal, 14(13), 1943-1952.