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

J Cardiovasc Electrophysiol. 2006 Mar;17(3):298-304. doi: 10.1111/j.1540-8167.2006.00362.x.


Background: Transient outward current (I(to)) and L-type calcium current (I(Ca)) 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 I(to) channel blockers, 4-aminopyridine (4-AP) and heteropodatoxin-2 (HpTx2), on I(Ca) in cardiac ventricular myocytes.

Methods and results: I(Ca) 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 I(Ca) 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 10 microM KN93, a specific inhibitor of CaMKII, abolished the effects of 4-AP on I(Ca.) To test the requirement of I(to), we studied guinea pig ventricular myocytes, which do not express I(to) channels. In these cells, 2 mM 4-AP had no effect on I(Ca) amplitude or kinetics. In both cell types, Ca2+-induced I(Ca) facilitation, a CaMKII-dependent process, was observed. However, 4-AP abolished Ca2+-induced I(Ca) facilitation exclusively in mouse ventricular myocytes.

Conclusion: 4-AP, an I(to) blocker, facilitates L-type Ca2+ current through a mechanism involving the I(to) channel and CaMKII activation. These data indicate a functional association of I(Ca) and I(to) in cardiac myocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine / pharmacology
  • Animals
  • Calcium Channels, L-Type / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Guinea Pigs
  • Heart Ventricles / cytology*
  • Heart Ventricles / metabolism
  • Ion Channel Gating / physiology
  • Mice
  • Neurotoxins / pharmacology
  • Patch-Clamp Techniques
  • Shal Potassium Channels / antagonists & inhibitors*
  • Spider Venoms / chemistry


  • Calcium Channels, L-Type
  • Neurotoxins
  • Shal Potassium Channels
  • Spider Venoms
  • 4-Aminopyridine
  • Calcium-Calmodulin-Dependent Protein Kinases