| 16643405 |
Wang Y, Cheng J, Tandan S, Jiang M, McCloskey DT, Hill JA: Transient-outward K+ channel inhibition facilitates L-type Ca2+ current in heart. J Cardiovasc Electrophysiol. 2006 Mar;17(3):298-304.
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. |
1(0,0,0,1) |