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An electrostatic potassium channel opener targeting the final voltage sensor transition.

Börjesson SI, Elinder F - J. Gen. Physiol. (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Sweden.

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.

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The lipoelectric mechanism and binding sites for other compounds. (A) Schematic illustration of the PUFA effect on the Shaker channel: negatively charged PUFAs shift the voltage dependence of a Kv channel in a negative direction along the voltage axis. (B) A PUFA binds with its hydrophobic acyl tail in the hydrophobic lipid bilayer or a hydrophobic pocket in the channel. From this position, the negatively charged carboxyl group of the PUFA electrostatically attracts the positively charged voltage sensor to open the intracellular gate of the ion channel. (C) Side view of the Kv1.2/2.1 chimera with Shaker side chains. Back and front domains are removed for clarity. Note that the VSDs and pore domains shown are from different subunits. Residues critical for quaternary ammonium compounds (Zhou et al., 2001) (I470 and V474 in green), pore-blocking toxins (MacKinnon et al., 1990) (D431, T449, and V451 in magenta), voltage sensor–trapping toxins (Swartz and MacKinnon, 1997) (L327, A328, and V331 in red), and retigabine (Lange et al., 2009) (I400, G406, V407, M440, and A464 in yellow) are shown as sticks. The gating charges R362, R365, R368, and R371 are marked as blue sticks. Residue numbering refers to Shaker.
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fig1: The lipoelectric mechanism and binding sites for other compounds. (A) Schematic illustration of the PUFA effect on the Shaker channel: negatively charged PUFAs shift the voltage dependence of a Kv channel in a negative direction along the voltage axis. (B) A PUFA binds with its hydrophobic acyl tail in the hydrophobic lipid bilayer or a hydrophobic pocket in the channel. From this position, the negatively charged carboxyl group of the PUFA electrostatically attracts the positively charged voltage sensor to open the intracellular gate of the ion channel. (C) Side view of the Kv1.2/2.1 chimera with Shaker side chains. Back and front domains are removed for clarity. Note that the VSDs and pore domains shown are from different subunits. Residues critical for quaternary ammonium compounds (Zhou et al., 2001) (I470 and V474 in green), pore-blocking toxins (MacKinnon et al., 1990) (D431, T449, and V451 in magenta), voltage sensor–trapping toxins (Swartz and MacKinnon, 1997) (L327, A328, and V331 in red), and retigabine (Lange et al., 2009) (I400, G406, V407, M440, and A464 in yellow) are shown as sticks. The gating charges R362, R365, R368, and R371 are marked as blue sticks. Residue numbering refers to Shaker.

Mentions: Polyunsaturated fatty acids (PUFAs) are components of phospholipids in the cell membrane, where they contribute to the fluidity and directly affect the activity of membrane proteins such as voltage-gated ion channels (Schmidt et al., 2006; Börjesson and Elinder, 2008; Y. Xu et al., 2008). In addition, free PUFAs play important physiological roles by affecting different membrane proteins, including ion channels (Boland and Drzewiecki, 2008; Sfondouris et al., 2008), and beneficial effects of PUFAs on heart arrhythmias and epilepsy have been reported (Lefevre and Aronson, 2000; Leaf et al., 2003). We suggested previously that PUFAs are important active substances in the fat-rich ketogenic diet used to treat severe epilepsy, by acting on voltage-gated K (Kv) channels (X.P. Xu et al., 2008). Specifically, PUFAs shift the voltage dependence of activation of the Shaker Kv channel via an electrostatic mechanism (Börjesson et al., 2008, 2010) (schematized in Fig. 1, A and B). Small shifts can have surprisingly large effects on excitability; a −5-mV shift is equivalent to increasing the number of K channels by a factor of 3 in the frog myelinated axon (Börjesson et al., 2010). The charge of the PUFA head group determines the direction of the effect, which has been referred to as the lipoelectric mechanism (Börjesson et al., 2008, 2010). However, because the site of action of PUFA on voltage-gated ion channels is unknown, the actual molecular mechanism of action for PUFA was hitherto unclear.


An electrostatic potassium channel opener targeting the final voltage sensor transition.

Börjesson SI, Elinder F - J. Gen. Physiol. (2011)

The lipoelectric mechanism and binding sites for other compounds. (A) Schematic illustration of the PUFA effect on the Shaker channel: negatively charged PUFAs shift the voltage dependence of a Kv channel in a negative direction along the voltage axis. (B) A PUFA binds with its hydrophobic acyl tail in the hydrophobic lipid bilayer or a hydrophobic pocket in the channel. From this position, the negatively charged carboxyl group of the PUFA electrostatically attracts the positively charged voltage sensor to open the intracellular gate of the ion channel. (C) Side view of the Kv1.2/2.1 chimera with Shaker side chains. Back and front domains are removed for clarity. Note that the VSDs and pore domains shown are from different subunits. Residues critical for quaternary ammonium compounds (Zhou et al., 2001) (I470 and V474 in green), pore-blocking toxins (MacKinnon et al., 1990) (D431, T449, and V451 in magenta), voltage sensor–trapping toxins (Swartz and MacKinnon, 1997) (L327, A328, and V331 in red), and retigabine (Lange et al., 2009) (I400, G406, V407, M440, and A464 in yellow) are shown as sticks. The gating charges R362, R365, R368, and R371 are marked as blue sticks. Residue numbering refers to Shaker.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105513&req=5

fig1: The lipoelectric mechanism and binding sites for other compounds. (A) Schematic illustration of the PUFA effect on the Shaker channel: negatively charged PUFAs shift the voltage dependence of a Kv channel in a negative direction along the voltage axis. (B) A PUFA binds with its hydrophobic acyl tail in the hydrophobic lipid bilayer or a hydrophobic pocket in the channel. From this position, the negatively charged carboxyl group of the PUFA electrostatically attracts the positively charged voltage sensor to open the intracellular gate of the ion channel. (C) Side view of the Kv1.2/2.1 chimera with Shaker side chains. Back and front domains are removed for clarity. Note that the VSDs and pore domains shown are from different subunits. Residues critical for quaternary ammonium compounds (Zhou et al., 2001) (I470 and V474 in green), pore-blocking toxins (MacKinnon et al., 1990) (D431, T449, and V451 in magenta), voltage sensor–trapping toxins (Swartz and MacKinnon, 1997) (L327, A328, and V331 in red), and retigabine (Lange et al., 2009) (I400, G406, V407, M440, and A464 in yellow) are shown as sticks. The gating charges R362, R365, R368, and R371 are marked as blue sticks. Residue numbering refers to Shaker.
Mentions: Polyunsaturated fatty acids (PUFAs) are components of phospholipids in the cell membrane, where they contribute to the fluidity and directly affect the activity of membrane proteins such as voltage-gated ion channels (Schmidt et al., 2006; Börjesson and Elinder, 2008; Y. Xu et al., 2008). In addition, free PUFAs play important physiological roles by affecting different membrane proteins, including ion channels (Boland and Drzewiecki, 2008; Sfondouris et al., 2008), and beneficial effects of PUFAs on heart arrhythmias and epilepsy have been reported (Lefevre and Aronson, 2000; Leaf et al., 2003). We suggested previously that PUFAs are important active substances in the fat-rich ketogenic diet used to treat severe epilepsy, by acting on voltage-gated K (Kv) channels (X.P. Xu et al., 2008). Specifically, PUFAs shift the voltage dependence of activation of the Shaker Kv channel via an electrostatic mechanism (Börjesson et al., 2008, 2010) (schematized in Fig. 1, A and B). Small shifts can have surprisingly large effects on excitability; a −5-mV shift is equivalent to increasing the number of K channels by a factor of 3 in the frog myelinated axon (Börjesson et al., 2010). The charge of the PUFA head group determines the direction of the effect, which has been referred to as the lipoelectric mechanism (Börjesson et al., 2008, 2010). However, because the site of action of PUFA on voltage-gated ion channels is unknown, the actual molecular mechanism of action for PUFA was hitherto unclear.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Sweden.

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.

Show MeSH
Related in: MedlinePlus