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Article ; Online: Alpha and omega in potassium-channel opening.

Elinder, Fredrik

2018 Volume 225, Issue 2, Page(s) e13240

MeSH term(s)	Calcium Channel Blockers ; Calcium Channels ; Fatty Acids, Unsaturated ; Potassium ; Potassium Channels
Chemical Substances	Calcium Channel Blockers ; Calcium Channels ; Fatty Acids, Unsaturated ; Potassium Channels ; Potassium (RWP5GA015D)
Language	English
Publishing date	2018-12-31
Publishing country	England
Document type	Editorial ; Comment
ZDB-ID	2218636-0
ISSN	1748-1716 ; 1748-1708
ISSN (online)	1748-1716
ISSN	1748-1708
DOI	10.1111/apha.13240
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Article ; Online: A quantitative model for human neurovascular coupling with translated mechanisms from animals.

Sten, Sebastian / Podéus, Henrik / Sundqvist, Nicolas / Elinder, Fredrik / Engström, Maria / Cedersund, Gunnar

PLoS computational biology

2023 Volume 19, Issue 1, Page(s) e1010818

Abstract: Neurons regulate the activity of blood vessels through the neurovascular coupling (NVC). A detailed understanding of the NVC is critical for understanding data from functional imaging techniques of the brain. Many aspects of the NVC have been studied ... ...

Abstract	Neurons regulate the activity of blood vessels through the neurovascular coupling (NVC). A detailed understanding of the NVC is critical for understanding data from functional imaging techniques of the brain. Many aspects of the NVC have been studied both experimentally and using mathematical models; various combinations of blood volume and flow, local field potential (LFP), hemoglobin level, blood oxygenation level-dependent response (BOLD), and optogenetics have been measured and modeled in rodents, primates, or humans. However, these data have not been brought together into a unified quantitative model. We now present a mathematical model that describes all such data types and that preserves mechanistic behaviors between experiments. For instance, from modeling of optogenetics and microscopy data in mice, we learn cell-specific contributions; the first rapid dilation in the vascular response is caused by NO-interneurons, the main part of the dilation during longer stimuli is caused by pyramidal neurons, and the post-peak undershoot is caused by NPY-interneurons. These insights are translated and preserved in all subsequent analyses, together with other insights regarding hemoglobin dynamics and the LFP/BOLD-interplay, obtained from other experiments on rodents and primates. The model can predict independent validation-data not used for training. By bringing together data with complementary information from different species, we both understand each dataset better, and have a basis for a new type of integrative analysis of human data.
MeSH term(s)	Humans ; Mice ; Animals ; Neurovascular Coupling/physiology ; Neurons/physiology ; Brain/physiology ; Pyramidal Cells ; Hemoglobins ; Cerebrovascular Circulation/physiology ; Magnetic Resonance Imaging/methods
Chemical Substances	Hemoglobins
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1010818
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Article ; Online: A quantitative analysis of cell-specific contributions and the role of anesthetics to the neurovascular coupling.

Sten, Sebastian / Elinder, Fredrik / Cedersund, Gunnar / Engström, Maria

NeuroImage

2020 Volume 215, Page(s) 116827

Abstract: The neurovascular coupling (NVC) connects neuronal activity to hemodynamic responses in the brain. This connection is the basis for the interpretation of functional magnetic resonance imaging data. Despite the central role of this coupling, we lack ... ...

Abstract	The neurovascular coupling (NVC) connects neuronal activity to hemodynamic responses in the brain. This connection is the basis for the interpretation of functional magnetic resonance imaging data. Despite the central role of this coupling, we lack detailed knowledge about cell-specific contributions and our knowledge about NVC is mainly based on animal experiments performed during anesthesia. Anesthetics are known to affect neuronal excitability, but how this affects the vessel diameters is not known. Due to the high complexity of NVC data, mathematical modeling is needed for a meaningful analysis. However, neither the relevant neuronal subtypes nor the effects of anesthetics are covered by current models. Here, we present a mathematical model including GABAergic interneurons and pyramidal neurons, as well as the effect of an anesthetic agent. The model is consistent with data from optogenetic experiments from both awake and anesthetized animals, and it correctly predicts data from experiments with different pharmacological modulators. The analysis suggests that no downstream anesthetic effects are necessary if one of the GABAergic interneuron signaling pathways include a Michaelis-Menten expression. This is the first example of a quantitative model that includes both the cell-specific contributions and the effect of an anesthetic agent on the NVC.
MeSH term(s)	Anesthetics/pharmacology ; Animals ; GABAergic Neurons/drug effects ; GABAergic Neurons/physiology ; Interneurons/drug effects ; Interneurons/physiology ; Mice ; Mice, Transgenic ; Models, Theoretical ; Neurovascular Coupling/drug effects ; Neurovascular Coupling/physiology ; Photic Stimulation/methods ; Pyramidal Cells/drug effects ; Pyramidal Cells/physiology
Chemical Substances	Anesthetics
Language	English
Publishing date	2020-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1147767-2
ISSN	1095-9572 ; 1053-8119
ISSN (online)	1095-9572
ISSN	1053-8119
DOI	10.1016/j.neuroimage.2020.116827
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Article ; Online: Coupling stabilizers open K

Silverå Ejneby, Malin / Wallner, Björn / Elinder, Fredrik

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 43, Page(s) 27016–27021

Abstract: The opening and closing of voltage-gated ion channels are regulated by voltage sensors coupled to a gate that controls the ion flux across the cellular membrane. Modulation of any part of gating constitutes an entry point for pharmacologically regulating ...

Abstract	The opening and closing of voltage-gated ion channels are regulated by voltage sensors coupled to a gate that controls the ion flux across the cellular membrane. Modulation of any part of gating constitutes an entry point for pharmacologically regulating channel function. Here, we report on the discovery of a large family of warfarin-like compounds that open the two voltage-gated type 1 potassium (K
MeSH term(s)	Animals ; High-Throughput Screening Assays ; Ion Channel Gating ; Kv1.5 Potassium Channel/agonists ; Kv1.5 Potassium Channel/metabolism ; Molecular Docking Simulation ; Patch-Clamp Techniques ; Shaker Superfamily of Potassium Channels/agonists ; Shaker Superfamily of Potassium Channels/metabolism ; Xenopus laevis
Chemical Substances	Kv1.5 Potassium Channel ; Shaker Superfamily of Potassium Channels
Language	English
Publishing date	2020-10-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2007965117
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Article: Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels.

Elinder, Fredrik / Liin, Sara I

Frontiers in physiology

2017 Volume 8, Page(s) 43

Abstract: Polyunsaturated fatty acids (PUFAs) act on most ion channels, thereby having significant physiological and pharmacological effects. In this review we summarize data from numerous PUFAs on voltage-gated ion channels containing one or several voltage- ... ...

Abstract	Polyunsaturated fatty acids (PUFAs) act on most ion channels, thereby having significant physiological and pharmacological effects. In this review we summarize data from numerous PUFAs on voltage-gated ion channels containing one or several voltage-sensor domains, such as voltage-gated sodium (Na
Language	English
Publishing date	2017-02-06
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2017.00043
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Article ; Online: Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1.

Elinder, Fredrik / Madeja, Michael / Zeberg, Hugo / Århem, Peter

Biophysical journal

2016 Volume 111, Issue 8, Page(s) 1679–1691

Abstract: The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels' voltage dependences to a large extent are set by charged amino-acid residues ... ...

Abstract	The transmembrane voltage needed to open different voltage-gated K (Kv) channels differs by up to 50 mV from each other. In this study we test the hypothesis that the channels' voltage dependences to a large extent are set by charged amino-acid residues of the extracellular linkers of the Kv channels, which electrostatically affect the charged amino-acid residues of the voltage sensor S4. Extracellular cations shift the conductance-versus-voltage curve, G(V), by interfering with these extracellular charges. We have explored these issues by analyzing the effects of the divalent strontium ion (Sr
MeSH term(s)	Animals ; Cell Membrane/metabolism ; Electrophysiological Phenomena ; Evolution, Molecular ; Extracellular Space/metabolism ; Kv1.2 Potassium Channel/metabolism ; Xenopus
Chemical Substances	Kv1.2 Potassium Channel
Language	English
Publishing date	2016-10-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2016.08.043
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Article ; Online: An electrostatic potassium channel opener targeting the final voltage sensor transition.

Börjesson, Sara I / Elinder, Fredrik

The Journal of general physiology

2011 Volume 137, Issue 6, Page(s) 563–577

Abstract: Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction ... ...

Abstract	Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction between PUFA and ion channels are not well understood. In this study, we have localized the site of action for PUFAs on the voltage-gated Shaker K channel by introducing positive charges on the channel surface, which potentiated the PUFA effect. Furthermore, we found that PUFA mainly affects the final voltage sensor movement, which is closely linked to channel opening, and that specific charges at the extracellular end of the voltage sensor are critical for the PUFA effect. Because different voltage-gated K channels have different charge profiles, this implies channel-specific PUFA effects. The identified site and the pharmacological mechanism will potentially be very useful in future drug design of small-molecule compounds specifically targeting neuronal and cardiac excitability.
MeSH term(s)	Amino Acid Sequence ; Animals ; Fatty Acids, Unsaturated/pharmacology ; Ion Transport/drug effects ; Membrane Potentials/physiology ; Models, Molecular ; Mutation ; Oocytes ; Potassium Channels, Voltage-Gated/metabolism ; Protein Conformation ; Protein Structure, Tertiary ; Static Electricity ; Xenopus laevis
Chemical Substances	Fatty Acids, Unsaturated ; Potassium Channels, Voltage-Gated
Language	English
Publishing date	2011-05-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.201110599
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Article ; Online: Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors.

Liin, Sara I / Lund, Per-Eric / Larsson, Johan E / Brask, Johan / Wallner, Björn / Elinder, Fredrik

The Journal of general physiology

2018 Volume 150, Issue 8, Page(s) 1215–1230

Abstract: Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more ... ...

Abstract	Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential-generating sodium and calcium channels and open an action potential-dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.
MeSH term(s)	Animals ; CHO Cells ; Cricetulus ; High-Throughput Screening Assays ; Kinetics ; Shaker Superfamily of Potassium Channels/drug effects ; Small Molecule Libraries ; Sulfonamides/pharmacology
Chemical Substances	Shaker Superfamily of Potassium Channels ; Small Molecule Libraries ; Sulfonamides
Language	English
Publishing date	2018-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.201711942
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Article ; Online: The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel.

Yazdi, Samira / Stein, Matthias / Elinder, Fredrik / Andersson, Magnus / Lindahl, Erik

PLoS computational biology

2016 Volume 12, Issue 1, Page(s) e1004704

Abstract: Voltage-gated potassium (KV) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which ...

Abstract	Voltage-gated potassium (KV) channels are membrane proteins that respond to changes in membrane potential by enabling K+ ion flux across the membrane. Polyunsaturated fatty acids (PUFAs) induce channel opening by modulating the voltage-sensitivity, which can provide effective treatment against refractory epilepsy by means of a ketogenic diet. While PUFAs have been reported to influence the gating mechanism by electrostatic interactions to the voltage-sensor domain (VSD), the exact PUFA-protein interactions are still elusive. In this study, we report on the interactions between the Shaker KV channel in open and closed states and a PUFA-enriched lipid bilayer using microsecond molecular dynamics simulations. We determined a putative PUFA binding site in the open state of the channel located at the protein-lipid interface in the vicinity of the extracellular halves of the S3 and S4 helices of the VSD. In particular, the lipophilic PUFA tail covered a wide range of non-specific hydrophobic interactions in the hydrophobic central core of the protein-lipid interface, while the carboxylic head group displayed more specific interactions to polar/charged residues at the extracellular regions of the S3 and S4 helices, encompassing the S3-S4 linker. Moreover, by studying the interactions between saturated fatty acids (SFA) and the Shaker KV channel, our study confirmed an increased conformational flexibility in the polyunsaturated carbon tails compared to saturated carbon chains, which may explain the specificity of PUFA action on channel proteins.
MeSH term(s)	Binding Sites ; Computational Biology ; Fatty Acids, Unsaturated/chemistry ; Fatty Acids, Unsaturated/metabolism ; Models, Molecular ; Shaker Superfamily of Potassium Channels/chemistry ; Shaker Superfamily of Potassium Channels/metabolism
Chemical Substances	Fatty Acids, Unsaturated ; Shaker Superfamily of Potassium Channels
Language	English
Publishing date	2016-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1004704
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Article ; Online: Drug-induced ion channel opening tuned by the voltage sensor charge profile.

Ottosson, Nina E / Liin, Sara I / Elinder, Fredrik

The Journal of general physiology

2014 Volume 143, Issue 2, Page(s) 173–182

Abstract: 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- ... ...

Abstract	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 µM DHA at pH 9.0 increased the current >500 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.
MeSH term(s)	Amino Acid Sequence ; Animals ; Docosahexaenoic Acids/pharmacology ; Female ; Ion Channel Gating/drug effects ; Ion Channel Gating/physiology ; Ion Channels/chemistry ; Ion Channels/physiology ; Molecular Sequence Data ; Mutation/physiology ; Shaker Superfamily of Potassium Channels/agonists ; Shaker Superfamily of Potassium Channels/chemistry ; Shaker Superfamily of Potassium Channels/physiology ; Xenopus laevis
Chemical Substances	Ion Channels ; Shaker Superfamily of Potassium Channels ; Docosahexaenoic Acids (25167-62-8)
Language	English
Publishing date	2014-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.201311087
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