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

Yousif A. Shamsaldeen; Lucy Culliford; Madeleine Clout; Andrew F. James; Raimondo Ascione; Jules C. Hancox; Neil V. Marrion

doi:10.1016/j.bbrc.2019.03.074

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

Yousif A. Shamsaldeen, Lucy Culliford, Madeleine Clout, Andrew F. James, Raimondo Ascione, Jules C. Hancox, Neil V. Marrion

Research output: Contribution to journal › Article › peer-review

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. Immuno-visualization 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.

Original language	English
Pages (from-to)	684-690
Number of pages	7
Journal	Biochemical and biophysical research communications
Volume	512
Issue number	4
DOIs	https://doi.org/10.1016/j.bbrc.2019.03.074
Publication status	Published - 25 Mar 2019

Bibliographical note

Funding Information:
The trial was funded by a Bristol Heart Foundation (BHF) grant ( BHF PG/16/37/ ) to Marrion, Hancox, James and Ascione. The study was also supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol . The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.

Keywords

Action potential
Atria
Heteromer
Human
Pharmacology
SK channel

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10.1016/j.bbrc.2019.03.074

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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. Immuno-visualization 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 = "Shamsaldeen, {Yousif A.} and Lucy Culliford and Madeleine Clout and James, {Andrew F.} and Raimondo Ascione and Hancox, {Jules C.} and Marrion, {Neil V.}",

note = "Funding Information: The trial was funded by a Bristol Heart Foundation (BHF) grant ( BHF PG/16/37/ ) to Marrion, Hancox, James and Ascione. The study was also supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol . The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care. ",

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doi = "10.1016/j.bbrc.2019.03.074",

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journal = "Biochemical and biophysical research communications",

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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 A.; Culliford, Lucy; Clout, Madeleine et al.
In: Biochemical and biophysical research communications, Vol. 512, No. 4, 25.03.2019, p. 684-690.

Research output: Contribution to journal › Article › peer-review

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AU - Shamsaldeen, Yousif A.

AU - Culliford, Lucy

AU - Clout, Madeleine

AU - James, Andrew F.

AU - Ascione, Raimondo

AU - Hancox, Jules C.

AU - Marrion, Neil V.

N1 - Funding Information: The trial was funded by a Bristol Heart Foundation (BHF) grant ( BHF PG/16/37/ ) to Marrion, Hancox, James and Ascione. The study was also supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol . The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care.

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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. Immuno-visualization 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. Immuno-visualization 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.

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JO - Biochemical and biophysical research communications

JF - Biochemical and biophysical research communications

IS - 4

ER -

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

Abstract

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Keywords

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