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Role of SK channel activation in determining the action potential configuration in freshly isolated human atrial myocytes from the SKArF Study

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Role of SK channel activation in determining the action potential configuration in freshly isolated human atrial myocytes from the SKArF Study. / Shamsaldeen, Yousif; Culliford, Lucy; Clout, Maddie; James, Andrew; Ascione, Raimondo; Hancox, Jules; Marrion, Neil.

In: Biochemical and Biophysical Research Communications, Vol. 512, No. 4, 14.05.2019, p. 684-690.

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@article{3cd134fe867f4cc29c24bca25b8396b0,
title = "Role of SK channel activation in determining the action potential configuration in freshly isolated human atrial myocytes from the SKArF Study",
abstract = "Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the atrial action potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the action potential waveform. Immunovisualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the atrial action potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as atrial fibrillation.",
keywords = "Action potential, Atria, Heteromer, Human, Pharmacology, SK channel",
author = "Yousif Shamsaldeen and Lucy Culliford and Maddie Clout and Andrew James and Raimondo Ascione and Jules Hancox and Neil Marrion",
year = "2019",
month = "5",
day = "14",
doi = "10.1016/j.bbrc.2019.03.074",
language = "English",
volume = "512",
pages = "684--690",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press",
number = "4",

}

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TY - JOUR

T1 - Role of SK channel activation in determining the action potential configuration in freshly isolated human atrial myocytes from the SKArF Study

AU - Shamsaldeen, Yousif

AU - Culliford, Lucy

AU - Clout, Maddie

AU - James, Andrew

AU - Ascione, Raimondo

AU - Hancox, Jules

AU - Marrion, Neil

PY - 2019/5/14

Y1 - 2019/5/14

N2 - Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the atrial action potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the action potential waveform. Immunovisualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the atrial action potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as atrial fibrillation.

AB - Inhibition of SK channel function is being pursued in animal models as a possible therapeutic approach to treat atrial fibrillation (AF). However, the pharmacology of SK channels in human atria is unclear. SK channel function is inhibited by both apamin and UCL1684, with the former discriminating between SK channel subtypes. In this proof-of-principle study, the effects of apamin and UCL1684 on right atrial myocytes freshly isolated from patients in sinus rhythm undergoing elective cardiac surgery were investigated. Outward current evoked from voltage clamped human atrial myocytes was reduced by these two inhibitors of SK channel function. In contrast, membrane current underlying the atrial action potential was affected significantly only by UCL1684 and not by apamin. This pharmacology mirrors that observed in mouse atria, suggesting that mammalian atria possess two populations of SK channels, with only one population contributing to the action potential waveform. Immunovisualization of the subcellular localization of SK2 and SK3 subunits showed a high degree of colocalization, consistent with the formation of heteromeric SK2/SK3 channels. These data reveal that human atrial myocytes express two SK channel subtypes, one exhibiting an unusual pharmacology. These channels contribute to the atrial action potential waveform and might be a target for novel therapeutic approaches to treat supraventricular arrhythmic conditions such as atrial fibrillation.

KW - Action potential

KW - Atria

KW - Heteromer

KW - Human

KW - Pharmacology

KW - SK channel

UR - http://www.scopus.com/inward/record.url?scp=85064514109&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2019.03.074

DO - 10.1016/j.bbrc.2019.03.074

M3 - Article

VL - 512

SP - 684

EP - 690

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 4

ER -