Repolarization and termination of the ventricular cardiac action potential is highly dependent on the activation of the slow delayed-rectifier potassium IKs channel. Disruption of the IKs current leads to the most common form of congenital long QT syndrome (LQTS), a disease that predisposes patients to ventricular arrhythmias and sudden cardiac death. We previously demonstrated that polyunsaturated fatty acid (PUFA) analogues increase outward K+ current in wild type and LQTS-causing mutant IKs channels. Our group has also demonstrated the necessity of a negatively charged PUFA head group for potent activation of the IKs channel through electrostatic interactions with the voltage-sensing and pore domains. Here, we test whether the efficacy of the PUFAs can be tuned by the presence of different functional groups in the PUFA head, thereby altering the electrostatic interactions of the PUFA head group with the voltage sensor or the pore. We show that PUFA analogues with taurine and cysteic head groups produced the most potent activation of IKs channels, largely by shifting the voltage dependence of activation. In comparison, the effect on voltage dependence of PUFA analogues with glycine and aspartate head groups was half that of the taurine and cysteic head groups, whereas the effect on maximal conductance was similar. Increasing the number of potentially negatively charged moieties did not enhance the effects of the PUFA on the IKs channel. Our results show that one can tune the efficacy of PUFAs on IKs channels by altering the pKa of the PUFA head group. Different PUFAs with different efficacy on IKs channels could be developed into more personalized treatments for LQTS patients with a varying degree of IKs channel dysfunction.
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December 19 2019
Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction
Briana M. Bohannon
,
Briana M. Bohannon
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
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Xiaoan Wu
,
Xiaoan Wu
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
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Xiongyu Wu
,
Xiongyu Wu
2
Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
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Marta E. Perez
,
Marta E. Perez
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
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Sara I. Liin
,
Sara I. Liin
3
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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H. Peter Larsson
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
Correspondence to H. Peter Larsson: plarsson@med.miami.edu
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Briana M. Bohannon
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
Xiaoan Wu
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
Xiongyu Wu
2
Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden
Marta E. Perez
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
Sara I. Liin
3
Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
H. Peter Larsson
1
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL
Correspondence to H. Peter Larsson: plarsson@med.miami.edu
J Gen Physiol (2020) 152 (2): e201912396.
Article history
Received:
May 08 2019
Revision Received:
September 05 2019
Revision Received:
November 22 2019
Accepted:
November 27 2019
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commentary-article:
A range of activators for cardiac IKs channels
Citation
Briana M. Bohannon, Xiaoan Wu, Xiongyu Wu, Marta E. Perez, Sara I. Liin, H. Peter Larsson; Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction. J Gen Physiol 3 February 2020; 152 (2): e201912396. doi: https://doi.org/10.1085/jgp.201912396
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