A disrupter of actin microfilaments impairs sulfonylurea-inhibitory gating of cardiac KATP channels

Peter A. Brady, Alexey E. Alekseev, Luba A. Aleksandrova, Luis A. Gomez, Andre Terzic

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

The efficacy with which sulfonylurea drugs inhibit cardiac ATP-sensitive K+ (KATP) channels is reduced during metabolic compromise and cellular contracture. Disruption of the actin microfilament network, which occurs under similar conditions, reduces the sensitivity of the channel toward intracellular ATP. To investigate whether a disrupter of actin microfilaments could also affect the responsiveness of the KATP channel to sulfonylurea drugs, single-channel currents were measured in the insideout configuration of excised patches from guinea pig ventricular myocytes. Treatment of the internal side of patches with deoxyribonuclease (DNase) I (100 μg/ml), which forms complexes with G actin and prevents actin filament formation, antagonized sulfonylurea-induced inhibition of KATP channels that was coupled with a loss of sensitivity to ATP. The apparent dissociation constant and Hill coefficient for the inhibitory effect of glyburide, a prototype sulfonylurea, on KATp-channel opening were, respectively, 0.13 uM and 0.95 before and 2.7 uM and 0.98 after DNase treatment. DNase did not alter intraburst kinetic properties of the channel. When DNase was denatured or coincubated with purified actin (200 μg/ml), it no longer decreased glyburide-induced channel inhibition. This suggests that sulfonylurea-inhibitory gating of cardiac KATP channels may also be regulated through a mechanism involving subsarcolemmal actin microfilament networks.

Original languageEnglish (US)
Pages (from-to)H2710-H2716
JournalAmerican Journal of Physiology
Volume271
Issue number6 PART 2
DOIs
StatePublished - 1996

Keywords

  • Adenosine 5'-triphosphate-sensitive potassium channels
  • Cytoskeleton
  • Deoxyribonuclease i
  • Glyburide
  • Heart

ASJC Scopus subject areas

  • Physiology (medical)

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