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

Full Abstract

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.

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Author information

Author/s: Wang, Yanggan (Y); Cheng, Jun (J); Tandan, Samvit (S); Jiang, Minjie (M); McCloskey, Diana T (DT); Hill, Joseph A (JA);

Affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. yanggan.wang(-atsign-)utsouthwestern.edu

Grants: HL-075173 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Journal of cardiovascular electrophysiology (J Cardiovasc Electrophysiol), published in United States. (Language: eng)

Reference: 2006-Mar; vol 17 (issue 3) : pp 298-304

Dates: Created 2006/04/28; Completed 2006/06/05; Revised 2007/11/15;

PMID: 16643405, status: MEDLINE (last retrieval date: 12/26/2008)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

4-Aminopyridine - pharmacology
Animals
Calcium Channels, L-Type - metabolism
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cell Membrane - drug effects; metabolism
Cells, Cultured
Guinea Pigs

Heart Ventricles - cytology; metabolism
Ion Channel Gating - physiology
Mice
Neurotoxins - pharmacology
Patch-Clamp Techniques
Shal Potassium Channels - antagonists & inhibitors
Spider Venoms - chemistry

Associated Chemicals: Calcium Channels, L-Type (0) ; Neurotoxins (0) ; Shal Potassium Channels (0) ; Spider Venoms (0) ; 4-Aminopyridine (504-24-5) ; Calcium-Calmodulin-Dependent Protein Kinases (EC 2.7.11.17)

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