Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues
Voltage-gated potassium (KV) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. KV channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-06-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/85773 |
| _version_ | 1797785175036264448 |
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| author | Briana M Bohannon Jessica J Jowais Leif Nyberg Vanessa Olivier-Meo Valentina Corradi D Peter Tieleman Sara I Liin H Peter Larsson |
| author_facet | Briana M Bohannon Jessica J Jowais Leif Nyberg Vanessa Olivier-Meo Valentina Corradi D Peter Tieleman Sara I Liin H Peter Larsson |
| author_sort | Briana M Bohannon |
| collection | DOAJ |
| description | Voltage-gated potassium (KV) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. KV channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore KV channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of KV channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac IKs channel – a tetrameric potassium channel complex formed by KV7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac IKs channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the IKs channel by generating modified aromatic head groups designed to probe cation–pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the IKs channel through cation–pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions. |
| first_indexed | 2024-03-13T00:51:19Z |
| format | Article |
| id | doaj.art-7551a63ea06f42c399ecf18db23a441f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-13T00:51:19Z |
| publishDate | 2023-06-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7551a63ea06f42c399ecf18db23a441f2023-07-07T15:18:50ZengeLife Sciences Publications LtdeLife2050-084X2023-06-011210.7554/eLife.85773Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analoguesBriana M Bohannon0Jessica J Jowais1Leif Nyberg2Vanessa Olivier-Meo3Valentina Corradi4D Peter Tieleman5https://orcid.org/0000-0001-5507-0688Sara I Liin6https://orcid.org/0000-0001-8493-0114H Peter Larsson7https://orcid.org/0000-0002-1688-2525Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United StatesDepartment of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United StatesDepartment of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United States; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United StatesDepartment of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, CanadaDepartment of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Calgary, CanadaDepartment of Biomedical and Clinical Sciences, Linköping University, Linköping, SwedenDepartment of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, United StatesVoltage-gated potassium (KV) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. KV channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore KV channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of KV channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac IKs channel – a tetrameric potassium channel complex formed by KV7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac IKs channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the IKs channel by generating modified aromatic head groups designed to probe cation–pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the IKs channel through cation–pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.https://elifesciences.org/articles/85773polyunsaturated fatty acidspotassium channellong QT syndrome |
| spellingShingle | Briana M Bohannon Jessica J Jowais Leif Nyberg Vanessa Olivier-Meo Valentina Corradi D Peter Tieleman Sara I Liin H Peter Larsson Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues eLife polyunsaturated fatty acids potassium channel long QT syndrome |
| title | Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues |
| title_full | Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues |
| title_fullStr | Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues |
| title_full_unstemmed | Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues |
| title_short | Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues |
| title_sort | mechanistic insights into robust cardiac iks potassium channel activation by aromatic polyunsaturated fatty acid analogues |
| topic | polyunsaturated fatty acids potassium channel long QT syndrome |
| url | https://elifesciences.org/articles/85773 |
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