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Ottosson, Nina
Publications (4 of 4) Show all publications
Silverå Ejneby, M., Wu, X., Ottosson, N., Münger, E. P., Lundström, I., Konradsson, P. & Elinder, F. (2018). Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid. The Journal of General Physiology, 150(5), 731-750
Open this publication in new window or tab >>Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid
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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
National Category
Physiology
Identifiers
urn:nbn:se:liu:diva-147837 (URN)10.1085/jgp.201711965 (DOI)000434417800008 ()2-s2.0-85046705149 (Scopus ID)
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
Ottosson, N. (2017). Molecular Mechanisms of Resin Acids and Their Derivatives on the Opening of a Potassium Channel. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Molecular Mechanisms of Resin Acids and Their Derivatives on the Opening of a Potassium Channel
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Voltage-gated ion channels play fundamental roles in excitable cells, such as neurons, where they enable electric signaling. Normally, this signaling is well controlled, but brain damage, alterations in the ionic composition of the extracellular solution, or dysfunctional ion channels can increase the electrical excitability thereby causing epilepsy. Voltage-gated ion channels are obvious targets for antiepileptic drugs, and, as a rule of thumb, excitability is dampened either by closing voltagegated sodium channels (Nav channels) or by opening voltage-gated potassium channels (Kv channels). For example, several classical antiepileptic drugs block the ion-conducting pore of Nav channels. Despite the large number of existing antiepileptic drugs, one third of the patients with epilepsy suffer from intractable or pharmacoresistant seizures.

Our research group has earlier described how different polyunsaturated fatty acids (PUFAs) open a Kv channel by binding close to the voltage sensor and, from this position, electrostatically facilitate the movement of the voltage-sensor, thereby opening the channel. However, PUFAs affect a wide range of ion channels, making it difficult to use them as pharmaceutical drugs; it would be desirable to find smallmolecule compounds with an electrostatic, PUFA-like mechanism of action. The aim of the research leading to this thesis was to find, characterize, and refine drug candidates capable of electrostatically opening a Kv channel.

The majority of the experiments were performed on the cloned Shaker Kv channel, expressed in oocytes from the frog Xenopus laevis, and the channel activity was explored with the two-electrode voltage-clamp technique. By systematically mutating the extracellular end of the channel’s voltage sensor, we constructed a highly PUFAsensitive channel, called the 3R channel. Such a channel is a useful tool in the search for electrostatic Kv-channel openers. We found that resin acids, naturally occurring in tree resins, act as electrostatic Shaker Kv channel openers. To explore the structure-activity relationship in detail, we synthesized 120 derivatives, whereof several were potent Shaker Kv channel openers. We mapped a common resin acidbinding site to a pocket formed by the voltage sensor, the channel’s third transmembrane segment, and the lipid membrane, a principally new binding site for small-molecule compounds. Further experiments showed that there are specific interactions between the compounds and the channel, suggesting promises for further drug development. Several of the most potent Shaker Kv channel openers also dampened the excitability in dorsal-root-ganglion neurons from mice, elucidating the pharmacological potency of these compounds. In conclusion, we have found that resin-acid derivatives are robust Kv-channel openers and potential drug candidates against diseases caused by hyperexcitability, such as epilepsy.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. p. 63
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1574
National Category
Clinical Medicine Chemical Sciences Medicinal Chemistry Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-136686 (URN)10.3384/diss.diva-136686 (DOI)9789176855218 (ISBN)
Public defence
2017-05-24, Berzeliussalen, Campus US, Linköping, 10:00 (English)
Opponent
Supervisors
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2018-01-25Bibliographically approved
Ottosson, N., Wu, X., Nolting, A., Karlsson, U., Lund, P.-E., Ruda, K., . . . Elinder, F. (2015). Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability. Scientific Reports, 5(13278)
Open this publication in new window or tab >>Resin-acid derivatives as potent electrostatic openers of voltage-gated K channels and suppressors of neuronal excitability
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 13278Article in journal (Refereed) Published
Abstract [en]

Voltage-gated ion channels generate cellular excitability, cause diseases when mutated, and act as drug targets in hyperexcitability diseases, such as epilepsy, cardiac arrhythmia and pain. Unfortunately, many patients do not satisfactorily respond to the present-day drugs. We found that the naturally occurring resin acid dehydroabietic acid (DHAA) is a potent opener of a voltage-gated K channel and thereby a potential suppressor of cellular excitability. DHAA acts via a non-traditional mechanism, by electrostatically activating the voltage-sensor domain, rather than directly targeting the ion-conducting pore domain. By systematic iterative modifications of DHAA we synthesized 71 derivatives and found 32 compounds more potent than DHAA. The most potent compound, Compound 77, is 240 times more efficient than DHAA in opening a K channel. This and other potent compounds reduced excitability in dorsal root ganglion neurons, suggesting that resin-acid derivatives can become the first members of a new family of drugs with the potential for treatment of hyperexcitability diseases.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Journals - Option C / Nature Publishing Group, 2015
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121307 (URN)10.1038/srep13278 (DOI)000359905300001 ()26299574 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Brain Foundation; Swedish Heart-Lung Foundation; ALF; County Council of Ostergotland

Available from: 2015-09-16 Created: 2015-09-14 Last updated: 2018-01-25Bibliographically approved
Ottosson, N., Liin, S. I. & Elinder, F. (2014). Drug-induced ion channel opening tuned by the voltage sensor charge profile. The Journal of General Physiology, 143(2), 173-182
Open this publication in new window or tab >>Drug-induced ion channel opening tuned by the voltage sensor charge profile
2014 (English)In: The Journal of General Physiology, ISSN 0022-1295, E-ISSN 1540-7748, Vol. 143, no 2, p. 173-182Article in journal (Refereed) Published
Abstract [en]

Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseases. Here, we show that arginines on one side of the helical K-channel voltage sensor S4 increased the sensitivity to docosahexaenoic acid (DHA), whereas arginines on the opposing side decreased this sensitivity. Glutamates had opposite effects. In addition, a positively charged DHA-like molecule, arachidonyl amine, had opposite effects to the negatively charged DHA. This suggests that S4 rotates to open the channel and that DHA electrostatically affects this rotation. A channel with arginines in positions 356, 359, and 362 was extremely sensitive to DHA: 70 mu M DHA at pH 9.0 increased the current greater than500 times at negative voltages compared with wild type (WT). The small-molecule compound pimaric acid, a novel Shaker channel opener, opened the WT channel. The 356R/359R/362R channel drastically increased this effect, suggesting it to be instrumental in future drug screening.

Place, publisher, year, edition, pages
Rockefeller University Press, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105035 (URN)10.1085/jgp.201311087 (DOI)000330628500006 ()
Available from: 2014-03-06 Created: 2014-03-06 Last updated: 2018-01-25
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