Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2

Alicia Lundby; Thomas Jespersen; Nicole Schmitt; Morten Grunnet; Søren-Peter Olesen; Jonathan M Cordeiro; Kirstine Calloe

doi:10.1111/j.1476-5381.2010.00859.x

Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2

Alicia Lundby, Thomas Jespersen, Nicole Schmitt, Morten Grunnet, Søren-Peter Olesen, Jonathan M Cordeiro, Kirstine Calloe

Molecular Cardiology and Membrane Proteins

34 Citations (Scopus)

Abstract

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.

Original language	English
Journal	British Journal of Pharmacology
Volume	160
Issue number	8
Pages (from-to)	2028-44
Number of pages	17
ISSN	0007-1188
DOIs	https://doi.org/10.1111/j.1476-5381.2010.00859.x
Publication status	Published - Aug 2010

Keywords

Animals
CHO Cells
Cloning, Molecular
Cricetinae
Cricetulus
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Humans
Ion Channel Gating
Kinetics
Kv Channel-Interacting Proteins
Kv1.4 Potassium Channel
Membrane Potentials
Nerve Tissue Proteins
Phenylurea Compounds
Potassium
Potassium Channels
Potassium Channels, Voltage-Gated
Shal Potassium Channels
Tetrazoles
Transfection
Xenopus laevis

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@article{b4e416049107427da0c0546cca0a2a4f,

title = "Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2",

abstract = "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.",

keywords = "Animals, CHO Cells, Cloning, Molecular, Cricetinae, Cricetulus, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Humans, Ion Channel Gating, Kinetics, Kv Channel-Interacting Proteins, Kv1.4 Potassium Channel, Membrane Potentials, Nerve Tissue Proteins, Phenylurea Compounds, Potassium, Potassium Channels, Potassium Channels, Voltage-Gated, Shal Potassium Channels, Tetrazoles, Transfection, Xenopus laevis",

author = "Alicia Lundby and Thomas Jespersen and Nicole Schmitt and Morten Grunnet and S{\o}ren-Peter Olesen and Cordeiro, {Jonathan M} and Kirstine Calloe",

year = "2010",

month = aug,

doi = "10.1111/j.1476-5381.2010.00859.x",

language = "English",

volume = "160",

pages = "2028--44",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "Wiley",

number = "8",

}

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 -

Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2

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Keywords

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