The actions of mdivi-1, an inhibitor of mitochondrial fission, on rapidly activating delayed-rectifier K+ current and membrane potential in HL-1 murine atrial cardiomyocytes

Edmund Cheung So, Chung-Hsi Hsing, Chia Hua Liang, Sheng Nan Wu

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Mdivi-1 is an inhibitor of dynamin related protein 1- (drp1)-mediated mitochondrial fission. However, the mechanisms through which this compound interacts directly with ion currents in heart cells remain unknown. In this study, its effects on ion currents and membrane potential in murine HL-1 cardiomyocytes were investigated. In whole-cell recordings, the addition of mdivi-1 decreased the amplitude of tail current (Itail) for the rapidly activating delayed-rectifier K+ current (IKr) in a concentration-dependent manner with an IC50 value at 11.6 μM, a value that resembles the inhibition requirement for mitochondrial division. It shifted the activation curve of Itail to depolarized voltages with no change in the gating charge. However, mdivi-1 did not alter the rate of recovery from current inactivation. In cell-attached configuration, mdivi-1 inside the pipette suppressed the activity of acetylcholine-activated K + channels without modifying the single-channel conductance. Mdivi-1 (30 μM) slightly depressed the peak amplitude of Na+ current with no change in the overall current-voltage relationship. Under current-clamp recordings, addition of mdivi-1 resulted in prolongation for the duration of action potentials (APs) and to increase the firing of spontaneous APs in HL-1 cells. Similarly, in pituitary GH3 cells, mdivi-1 was effective in directly suppressing the amplitude of ether-à-go-go-related gene-mediated K+ current. Therefore, the lengthening of AP duration and increased firing of APs caused by mdivi-1 can be primarily explained by its inhibition of these K+ channels enriched in heart cells. The observed effects of mdivi-1 on ion currents were direct and not associated with its inhibition of mitochondrial division.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalEuropean Journal of Pharmacology
Volume683
Issue number1-3
DOIs
Publication statusPublished - May 15 2012

Keywords

  • Cardiomyocyte
  • Inhibitor of mitochondrial division
  • Muscarinic K channel
  • Rapidly activating K current

ASJC Scopus subject areas

  • Pharmacology

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