Transient-outward K+ channel inhibition facilitates L-type Ca2+ current in heart

Yanggan Wang, Jun Cheng, Samvit Tandan, Minjie Jiang, Diana T. McCloskey, Joseph A. Hill

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Background: Transient outward current (Ito) and L-type calcium current (ICa) are important repolarization currents in cardiac myocytes. These two currents often undergo disease-related remodeling while other currents are spared, suggesting a functional coupling between them. Here, we investigated the effects of Ito channel blockers, 4-aminopyridine (4-AP) and heteropodatoxin-2 (HpTx2), on ICa in cardiac ventricular myocytes. Methods and Results: ICa was recorded in enzymatically dissociated mouse and guinea pig ventricular myocytes using the whole-cell voltage clamp method. In mouse ventricular myocytes, 4-AP (2 mM) significantly facilitated ICa by increasing current amplitude and slowing inactivation. These effects were not voltage-dependent. Similar facilitating effects were seen when equimolar Ba2+ was substituted for external Ca2+, indicating that Ca2+ influx is not required. Measurements of Ca2+/calmodulin-dependent protein kinase (CaMKII) activity revealed significant increases in cells treated with 4-AP. Pretreatment of cells with 10μM KN93, a specific inhibitor of CaMKII, abolished the effects of 4-AP on ICa. To test the requirement of Ito, we studied guinea pig ventricular myocytes, which do not express Ito channels. In these cells, 2 mM 4-AP had no effect on ICa amplitude or kinetics. In both cell types, Ca2+-induced ICa facilitation, a CaMKII-dependent process, was observed. However, 4-AP abolished Ca2+-induced ICa facilitation exclusively in mouse ventricular myocytes. Conclusion: 4-AP, an Ito blocker, facilitates L-type Ca2+ current through a mechanism involving the Ito channel and CaMKII activation. These data indicate a functional association of ICa and Ito in cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)298-304
Number of pages7
JournalJournal of Cardiovascular Electrophysiology
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2006

Keywords

  • 4-aminopyridine
  • Heteropodatoxin
  • Ion channels
  • L-type calcium current
  • Transient outward current
  • Ventricular myocytes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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