ATP-sensitive K+ channel channel/enzyme multimer: Metabolic gating in the heart

Alexey E. Alekseev, Denice M. Hodgson, Amy B. Karger, Sungjo Park, Leonid V. Zingman, Andre Terzic

Research output: Contribution to journalReview articlepeer-review

78 Scopus citations

Abstract

Cardiac ATP-sensitive K+ (KATP) channels, gated by cellular metabolism, are formed by association of the inwardly rectifying potassium channel Kir6.2, the potassium conducting subunit, and SUR2A, the ATP-binding cassette protein that serves as the regulatory subunit. Kir6.2 is the principal site of ATP-induced channel inhibition, while SUR2A regulates K+ flux through adenine nucleotide binding and catalysis. The ATPase-driven conformations within the regulatory SUR2A subunit of the K ATP channel complex have determinate linkage with the states of the channel's pore. The probability and life-time of ATPase-induced SUR2A intermediates, rather than competitive nucleotide binding alone, defines nucleotide-dependent KATP channel gating. Cooperative interaction, instead of independent contribution of individual nucleotide binding domains within the SUR2A subunit, serves a decisive role in defining KATP channel behavior. Integration of KATP channels with the cellular energetic network renders these channel/enzyme heteromultimers high-fidelity metabolic sensors. This vital function is facilitated through phosphotransfer enzyme-mediated transmission of controllable energetic signals. By virtue of coupling with cellular energetic networks and the ability to decode metabolic signals, KATP channels set membrane excitability to match demand for homeostatic maintenance. This new paradigm in the operation of an ion channel multimer is essential in providing the basis for KATP channel function in the cardiac cell, and for understanding genetic defects associated with life-threatening diseases that result from the inability of the channel complex to optimally fulfill its physiological role.

Original languageEnglish (US)
Pages (from-to)895-905
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume38
Issue number6
DOIs
StatePublished - Jun 2005

Keywords

  • ATP-binding cassette
  • Action potential
  • Adenylate kinase
  • Creatine kinase
  • Eneregetics
  • Glycolysis
  • Heart failure
  • K channel
  • Kir6.2
  • Knock-out
  • Nucleotide
  • Phosphotransfer
  • Potassium channel opener
  • SUR2A
  • Sulfonylurea receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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