KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site
The voltage-gated potassium channel KV7.1 and the auxiliary subunit KCNE1 together form the cardiac IKs channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate KV7.1 via an electrostatic mechanism. The activating ef...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/37257 |
| _version_ | 1811235924419280896 |
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| author | Johan E Larsson H Peter Larsson Sara I Liin |
| author_facet | Johan E Larsson H Peter Larsson Sara I Liin |
| author_sort | Johan E Larsson |
| collection | DOAJ |
| description | The voltage-gated potassium channel KV7.1 and the auxiliary subunit KCNE1 together form the cardiac IKs channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate KV7.1 via an electrostatic mechanism. The activating effect was abolished when KV7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation. Here, we found that neutralization of negatively charged residues in the S5-P-helix loop of KV7.1 restored PUFA effects on KV7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of KV7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on KV7.1. This mechanistic understanding of how KCNE1 alters KV7.1 pharmacology is essential for development of drugs targeting the IKs channel. |
| first_indexed | 2024-04-12T12:00:26Z |
| format | Article |
| id | doaj.art-76afcc4292c34739b5d68f68e35d6b4e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:00:26Z |
| publishDate | 2018-07-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj.art-76afcc4292c34739b5d68f68e35d6b4e2022-12-22T03:33:52ZengeLife Sciences Publications LtdeLife2050-084X2018-07-01710.7554/eLife.37257KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding siteJohan E Larsson0https://orcid.org/0000-0003-3852-1015H Peter Larsson1https://orcid.org/0000-0002-1688-2525Sara I Liin2https://orcid.org/0000-0001-8493-0114Department of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Physiology and Biophysics, University of Miami, Miami, United StatesDepartment of Clinical and Experimental Medicine, Linköping University, Linköping, SwedenThe voltage-gated potassium channel KV7.1 and the auxiliary subunit KCNE1 together form the cardiac IKs channel, which is a proposed target for future anti-arrhythmic drugs. We previously showed that polyunsaturated fatty acids (PUFAs) activate KV7.1 via an electrostatic mechanism. The activating effect was abolished when KV7.1 was co-expressed with KCNE1, as KCNE1 renders PUFAs ineffective by promoting PUFA protonation. PUFA protonation reduces the potential of PUFAs as anti-arrhythmic compounds. It is unknown how KCNE1 promotes PUFA protonation. Here, we found that neutralization of negatively charged residues in the S5-P-helix loop of KV7.1 restored PUFA effects on KV7.1 co-expressed with KCNE1 in Xenopus oocytes. We propose that KCNE1 moves the S5-P-helix loop of KV7.1 towards the PUFA-binding site, which indirectly causes PUFA protonation, thereby reducing the effect of PUFAs on KV7.1. This mechanistic understanding of how KCNE1 alters KV7.1 pharmacology is essential for development of drugs targeting the IKs channel.https://elifesciences.org/articles/37257KCNQ1protonationtwo-electrode voltage clampIKs |
| spellingShingle | Johan E Larsson H Peter Larsson Sara I Liin KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site eLife KCNQ1 protonation two-electrode voltage clamp IKs |
| title | KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site |
| title_full | KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site |
| title_fullStr | KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site |
| title_full_unstemmed | KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site |
| title_short | KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site |
| title_sort | kcne1 tunes the sensitivity of kv7 1 to polyunsaturated fatty acids by moving turret residues close to the binding site |
| topic | KCNQ1 protonation two-electrode voltage clamp IKs |
| url | https://elifesciences.org/articles/37257 |
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