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- W3130110568 abstract "Polyunsaturated fatty acids (PUFAs) affect many ion channels and have been proposed to have anti-epileptic and anti-arrhythmic effects in the brain and the heart. However, the molecular mechanism behind these effects are not completely understood. This limits the possibility to infer the impact of PUFAs on ion channel function and impedes rational development of anti-epileptic and anti-arrhythmic drugs based on PUFAs. We have used electrophysiology techniques in combination with molecular dynamics simulations and synthetic chemistry to determine the molecular mechanism of how PUFAs and their analogues facilitate activation of the cardiac Kv7.1 channel. Kv7.1 (also called KCNQ1) together with the beta subunit KCNE1 form voltage-gated potassium channels that generate the important repolarizing IKs current in the heart. Loss-of-function mutations in the genes encoding Kv7.1 or KCNE1 can prolong the QT interval in the electrocardiogram and cause Long QT Syndrome, which predisposes people to cardiac arrhythmia and sudden cardiac death. We find that PUFAs and PUFA analogues activate the Kv7.1 channel by shifting the voltage dependence of channel opening towards more negative voltages and increasing the maximal conductance. These two activating effects are independent of each other and mediated by PUFA interaction with two distinct sites in the channel. We have identified components of both the PUFA molecule and Kv7.1 critical for activating effects, which provides an understanding of fatty acid selectivity mechanisms and facilitates rational design of PUFA analogues with improved effect. We anticipate that the molecular understanding of how PUFA analogues activate the Kv7.1 channel will allow for future development of more effective anti-arrhythmic drugs based on PUFA analogues." @default.
- W3130110568 created "2021-03-01" @default.
- W3130110568 creator A5066835694 @default.
- W3130110568 date "2021-02-01" @default.
- W3130110568 modified "2023-09-25" @default.
- W3130110568 title "Rational Design of Fatty Acid Analogues Targeting the Cardiac KV7.1 Channel" @default.
- W3130110568 doi "https://doi.org/10.1016/j.bpj.2020.11.897" @default.
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