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Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering.
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2018 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 150, no 5, p. 731-750Article in journal (Refereed) Published
Abstract [en]

Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel’s positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel’s voltage sensor, leading to the channel opening. In this study, we show that the channel-opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 µM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug.

Place, publisher, year, edition, pages
New York, United States: Rockefeller Institute for Medical Research , 2018. Vol. 150, no 5, p. 731-750
National Category
Physiology
Identifiers
URN: urn:nbn:se:liu:diva-147837DOI: 10.1085/jgp.201711965ISI: 000434417800008Scopus ID: 2-s2.0-85046705149OAI: oai:DiVA.org:liu-147837DiVA, id: diva2:1205882
Note

Funding agencies: Swedish Research Council [2016-02615]; Swedish Heart-Lung Foundation [20150672]; Swedish Brain Foundation [2016-0326]

Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2018-06-28Bibliographically approved
In thesis
1. Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels
Open this publication in new window or tab >>Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels are pore-forming membrane proteins that open or close their gates when the voltage across the membrane is changed. They underlie the electrical activity that enables the heart to pump blood and the brain to receive and send signals. Changes in expression, distribution, and functional properties of voltage-gated ion channels can lead to diseases, such as epilepsy, cardiac arrhythmia, and pain-related disorders. Drugs that modulate the function of voltage-gated ion channels control these diseases in some patients, but the existing drugs do not adequately help all patients, and some also have severe side effects.

Resin acids are common components of pine resins, with a hydrophobic three-ringed motif and a negatively charged carboxyl group. They open big-conductance Ca2+-activated K+ (BK) channels and voltage-gated potassium (KV) channels. We aimed to characterize the binding site and mechanism of action of resin acids on a KV channel and explore the effect of a resin acid by modifying the position and valence of charge of the carboxyl group. We tested the effect on several voltage-gated ion channels, including two KV channels expressed in Xenopus laevis oocytes and several voltage-gated ion channels expressed in cardiomyocytes. For this endeavour different electrophysiological techniques, ion channels, and cell types were used together with chemical synthesis of about 140 resin-acid derivatives, mathematical models, and computer simulations.

We found that resin acids bind between the lipid bilayer and the Shaker KV channel, in the cleft between transmembrane segment S3 and S4, on the extracellular side of the voltage-sensor domain. This is a fundamentally new interaction site for small-molecule compounds that otherwise usually bind to ion channels in pockets surrounded by water. We also showed that the resin acids open the Shaker KV channel via an electrostatic mechanism, exerted on the positively charged voltage sensor S4. The effect of a resin acid increased when the negatively charged carboxyl group (the effector) and the hydrophobic three-ringed motif (anchor in lipid bilayer) were separated by three atoms: longer stalks decreased the effect. The length rule, in combination with modifications of the anchor, was used to design new resin-acid derivatives that open the human M-type (Kv7.2/7.3) channel. A naturally occurring resin acid also reduced the excitability of cardiomyocytes by affecting the voltage-dependence of several voltage-gated ion channels. The major finding was that the resin acid inactivated sodium and calcium channels, while it activated KV channels at more negative membrane voltages. Computer simulations confirmed that the combined effect on different ion channels reduced the excitability of a cardiomyocyte. Finally, the resin acid reversed induced arrhythmic firing of the cardiomyocytes.

In conclusion, resin acids are potential drug candidates for diseases such as epilepsy and cardiac arrhythmia: knowing the binding site and mechanism of action can help to fine tune the resin acid to increase the effect, as well as the selectivity.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 50
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1620
National Category
Biophysics Biochemistry and Molecular Biology Pharmaceutical Sciences Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-147838 (URN)10.3384/diss.diva-147838 (DOI)9789176853184 (ISBN)
Public defence
2018-06-05, Hasselquistsalen, Campus US, Linköping, 13:00 (English)
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Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2019-09-30Bibliographically approved

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Silverå Ejneby, MalinWu, XiongyuOttosson, NinaMünger, E PeterLundström, IngemarKonradsson, PeterElinder, Fredrik

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