TY - JOUR
T1 - Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2
AU - Lundby, Alicia
AU - Jespersen, Thomas
AU - Schmitt, Nicole
AU - Grunnet, Morten
AU - Olesen, Søren-Peter
AU - Cordeiro, Jonathan M
AU - Calloe, Kirstine
PY - 2010/8
Y1 - 2010/8
N2 - BACKGROUND AND PURPOSE The compound NS5806 increases the transient outward current (I to) in canine ventricular cardiomyocytes and slows current decay. In human and canine ventricle, I to is thought to be mediated by K V4.3 and various ancillary proteins, yet, the exact subunit composition of I to channels is still debated. Here we characterize the effect of NS5806 on heterologously expressed putative I to channel subunits and other potassium channels. EXPERIMENTAL APPROACH Cloned K V4 channels were co-expressed with KChIP2, DPP6, DPP10, KCNE2, KCNE3 and K V1.4 in Xenopus laevis oocytes or CHO-K1 cells. KEY RESULTS NS5806 increased K V4.3/KChIP2 peak current amplitudes with an EC 50 of 5.3 ± 1.5M and significantly slowed current decay. KCNE2, KCNE3, DPP6 and DPP10 modulated K V4.3 currents and the response to NS5806, but current decay was slowed only in complexes containing KChIP2. The effect of NS5806 on K V4.2 was similar to that on K V4.3, and current decay was only slowed in presence of KChIP2. However, for K V4.1, the slowing of current decay by NS5806 was independent of KChIP2. K V1.4 was strongly inhibited by 10 M NS5806 and K V1.5 was inhibited to a smaller extent. Effects of NS5806 on kinetics of currents generated by K V4.3/KChIP2/DPP6 with K V1.4 in oocytes could reproduce those on cardiac I to in canine ventricular myocytes. K V7.1, K V11.1 and K ir2 currents were unaffected by NS5806. CONCLUSION AND IMPLICATIONS NS5806 modulated K V4 channel gating depending on the presence of KChIP2, suggesting that NS5806 can potentially be used to address the molecular composition as well as the physiological role of cardiac I to.
AB - BACKGROUND AND PURPOSE The compound NS5806 increases the transient outward current (I to) in canine ventricular cardiomyocytes and slows current decay. In human and canine ventricle, I to is thought to be mediated by K V4.3 and various ancillary proteins, yet, the exact subunit composition of I to channels is still debated. Here we characterize the effect of NS5806 on heterologously expressed putative I to channel subunits and other potassium channels. EXPERIMENTAL APPROACH Cloned K V4 channels were co-expressed with KChIP2, DPP6, DPP10, KCNE2, KCNE3 and K V1.4 in Xenopus laevis oocytes or CHO-K1 cells. KEY RESULTS NS5806 increased K V4.3/KChIP2 peak current amplitudes with an EC 50 of 5.3 ± 1.5M and significantly slowed current decay. KCNE2, KCNE3, DPP6 and DPP10 modulated K V4.3 currents and the response to NS5806, but current decay was slowed only in complexes containing KChIP2. The effect of NS5806 on K V4.2 was similar to that on K V4.3, and current decay was only slowed in presence of KChIP2. However, for K V4.1, the slowing of current decay by NS5806 was independent of KChIP2. K V1.4 was strongly inhibited by 10 M NS5806 and K V1.5 was inhibited to a smaller extent. Effects of NS5806 on kinetics of currents generated by K V4.3/KChIP2/DPP6 with K V1.4 in oocytes could reproduce those on cardiac I to in canine ventricular myocytes. K V7.1, K V11.1 and K ir2 currents were unaffected by NS5806. CONCLUSION AND IMPLICATIONS NS5806 modulated K V4 channel gating depending on the presence of KChIP2, suggesting that NS5806 can potentially be used to address the molecular composition as well as the physiological role of cardiac I to.
KW - Animals
KW - CHO Cells
KW - Cloning, Molecular
KW - Cricetinae
KW - Cricetulus
KW - Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
KW - Humans
KW - Ion Channel Gating
KW - Kinetics
KW - Kv Channel-Interacting Proteins
KW - Kv1.4 Potassium Channel
KW - Membrane Potentials
KW - Nerve Tissue Proteins
KW - Phenylurea Compounds
KW - Potassium
KW - Potassium Channels
KW - Potassium Channels, Voltage-Gated
KW - Shal Potassium Channels
KW - Tetrazoles
KW - Transfection
KW - Xenopus laevis
U2 - 10.1111/j.1476-5381.2010.00859.x
DO - 10.1111/j.1476-5381.2010.00859.x
M3 - Journal article
C2 - 20649599
SN - 0007-1188
VL - 160
SP - 2028
EP - 2044
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 8
ER -