Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues
- Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, United States
- Department of Biomedical and Clinical Sciences, Linköping University, Sweden
- Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary, Canada
Figures
Figure 1
Polyunsaturated fatty acids (PUFA) analogues with a tyrosine head group are strong IKs channel activators.
(A) Schematic of two electrode voltage-clamp setup (inset: IKs channel cartoon + PUFA [pink]). (B) Voltage protocol (top) with representative KV7.1/KCNE1 (IKs) current (bottom). (C) Structures of …
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Figure 1—source data 1
Source Data for Panels D-F.
- https://cdn.elifesciences.org/articles/85773/elife-85773-fig1-data1-v2.docx
Figure 2
The distal hydroxyl (–OH) group of tyrosine polyunsaturated fatty acid (PUFA) analogues is necessary for robust IKs channel activation.
(A) Structures of NAL-phe and Lin-phe. (B) Representative current traces for NALT (gray), NAL-phe (black), Lin-tyr (pink), and Lin-phe with 0 μM PUFA (left) and 20 μM PUFA (right). (C, E, G) I/I0, (E…
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Figure 2—source data 1
Source Data for Panels C-H.
- https://cdn.elifesciences.org/articles/85773/elife-85773-fig2-data1-v2.docx
Figure 3
The addition of electronegative atoms to phenylalanine polyunsaturated fatty acid (PUFA) analogues strengthens IKs channel activation through improved effects on Gmax.
(A) Structures of 4Br-NAL-phe, 4F-NAL-phe, and 3,4,5F-NAL-phe. (B) Representative traces for 4Br-NAL-phe (pink), 4F-NAL-phe (teal), and 3,4,5F-NAL-phe (purple) with 0 μM PUFA (left) and 20 μM PUFA …
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Figure 3—source data 1
Source Data for Panels C-H.
- https://cdn.elifesciences.org/articles/85773/elife-85773-fig3-data1-v2.docx
Figure 4
Hydrogen bonding through the distal –OH group of tyrosine polyunsaturated fatty acids (PUFAs) is important for effects on IKs channel voltage dependence.
(A) Structures of NALT and 3F-NALT. (B) Representative traces of NALT (gray) and 3F-NALT (cyan) with 0 μM PUFA (left) and 20 μM PUFA (right). (C, E, G) I/I0, (E) ΔV0.5, and (G) Gmax dose–response …
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Figure 4—source data 1
Source Data for Panels C-H.
- https://cdn.elifesciences.org/articles/85773/elife-85773-fig4-data1-v2.docx
Figure 5
Proposed mechanisms of aromatic polyunsaturated fatty acids (PUFAs).
(A) Structure of KV7.1 voltage-sensing domain (VSD) based on PDB: 6V00A projected using PyMOL Software (Schrödinger L and DeLano 2020). Pink spheres indicate mutated residues in the S4 segment, …
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Figure 5—source data 1
Source Data for Panels B, C, E, F, G, and H.
- https://cdn.elifesciences.org/articles/85773/elife-85773-fig5-data1-v2.docx
Figure 6
Loop is the locus for hydrogen bonding interactions with tyrosine polyunsaturated fatty acids (PUFAs).
(A) Top view of KV7.1 voltage-sensing domain (VSD) highlighting mutated residues in the S3–S4 loop. (B) Representative traces of WT KV7.1/KCNE1 (black), KV7.1-S217A/KCNE1 (red), KV7.1-Q220L/KCNE1 …
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Figure 6—source data 1
Source Data for Panel C, D, F, and G.
- https://cdn.elifesciences.org/articles/85773/elife-85773-fig6-data1-v2.docx
Figure 7
Model for aromatic polyunsaturated fatty acid (PUFA) interaction with Kv7.1/KCNE1 channels.
(A) Image of the KCNQ1 structure (PDB 6UZZ) marking the distance between R231 and T224. This distance is shown in comparison to the length of a tyrosine head group. (B) Model for aromatic PUFAs …
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