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Mechanistic insights into robust cardiac I-Ks potassium channel activation by aromatic polyunsaturated fatty acid analogues
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- Bohannon, Briana M. (author)
- Univ Miami, FL 33136 USA
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- Jowais, Jessica J. (author)
- Univ Miami, FL 33136 USA
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- Nyberg, Leif (author)
- Linköpings universitet,Institutionen för biomedicinska och kliniska vetenskaper,Medicinska fakulteten,Univ Miami, FL 33136 USA
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- Olivier-Meo, Vanessa (author)
- Univ Miami, FL 33136 USA
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- Corradi, Valentina (author)
- Univ Calgary, Canada
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- Tieleman, D. Peter (author)
- Univ Calgary, Canada
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- Liin, Sara (author)
- Linköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten
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- Larsson, H. Peter (author)
- Univ Miami, FL 33136 USA
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(creator_code:org_t)
- eLIFE SCIENCES PUBL LTD, 2023
- 2023
- English.
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In: eLIFE. - : eLIFE SCIENCES PUBL LTD. - 2050-084X. ; 12
- Related links:
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.7...
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Abstract
Subject headings
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- Voltage-gated potassium (K-V) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K-V 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 K-V channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K-V 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 I-Ks channel - a tetrameric potassium channel complex formed by K(V)7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I-Ks 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 I-Ks 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 I-Ks channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.
Subject headings
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
Keyword
- polyunsaturated fatty acids; potassium channel; long QT syndrome
Publication and Content Type
- ref (subject category)
- art (subject category)
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