Ligand-insensitive state of cardiac ATP-sensitive K+ channels: Basis for channel opening

Alexey E. Alekseev, Peter A. Brady, Andre Terzic

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

The mechanism by which ATP-sensitive K- (K(ATP)) channels open in the presence of inhibitory concentrations of ATP remains unknown. Herein, using a four-state kinetic model, we found that the nucleotide diphosphate UDP directed cardiac K(ATP) channels to operate within intraburst transitions. These transitions are not targeted by ATP, nor the structurally unrelated sulfonylurea glyburide, which inhibit channel opening by acting on interburst transitions. Therefore, the channel remained insensitive to ATP and glyburide in the presence of UDP. 'Rundown' of channel activity decreased the efficacy with which UDP could direct and maintain the channel to operate within intraburst transitions. Under this condition, the channel was sensitive to inhibition by ATP and glyburide despite the presence of UDP. This behavior of the K(ATP) channel could be accounted for by an allosteric model of ligand- channel interaction. Thus, the response of cardiac K(ATP) channels towards inhibitory ligands is determined by the relative lifetime the channel spends in a ligand-sensitive versus-insensitive state. Interconversion between these two conformational states represents a novel basis for K(ATP) channel opening in the presence of inhibitory concentrations of ATP in a cardiac cell.

Original languageEnglish (US)
Pages (from-to)381-394
Number of pages14
JournalJournal of General Physiology
Volume111
Issue number2
DOIs
StatePublished - Feb 1998

Keywords

  • Allosteric model
  • K(ATP) channel
  • Kinetic model
  • Nucleotide diphosphate
  • Sulfonylurea

ASJC Scopus subject areas

  • Physiology

Fingerprint Dive into the research topics of 'Ligand-insensitive state of cardiac ATP-sensitive K<sup>+</sup> channels: Basis for channel opening'. Together they form a unique fingerprint.

Cite this