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In-Depth Study of the Interaction, Sensitivity, and Gating Modulation by PUFAs on K + Channels; Interaction and New Targets

View Article: PubMed Central - PubMed

ABSTRACT

Voltage gated potassium channels (KV) are membrane proteins that allow selective flow of K+ ions in a voltage-dependent manner. These channels play an important role in several excitable cells as neurons, cardiomyocytes, and vascular smooth muscle. Over the last 20 years, it has been shown that omega-3 polyunsaturated fatty acids (PUFAs) enhance or decrease the activity of several cardiac KV channels. PUFAs-dependent modulation of potassium ion channels has been reported to be cardioprotective. However, the precise cellular mechanism underlying the cardiovascular benefits remained unclear in part because new PUFAs targets and signaling pathways continue being discovered. In this review, we will focus on recent data available concerning the following aspects of the KV channel modulation by PUFAs: (i) the exact residues involved in PUFAs-KV channels interaction; (ii) the structural PUFAs determinants important for their effects on KV channels; (iii) the mechanism of the gating modulation of KV channels and, finally, (iv) the PUFAs modulation of a few new targets present in smooth muscle cells (SMC), KCa1.1, K2P, and KATP channels, involved in vascular relaxation.

No MeSH data available.


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Effects of EPA in membrane cholesterol-depleted cells with methyl-β-cyclodextrin (MβCD). (A) Current records obtained from the same cell and generated by KV7.1-KCNE1 channels in control, after perfusion with MβCD, with EPA and after washout the cells with EPA-free external solution. (B) Current-voltage relationships under all conditions shown in (A). (C) Plot showing the voltage dependence of the MβCD and EPA effects (D) Activation curves and (E) normalized activation curves. Moreno et al. (2015).
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Figure 4: Effects of EPA in membrane cholesterol-depleted cells with methyl-β-cyclodextrin (MβCD). (A) Current records obtained from the same cell and generated by KV7.1-KCNE1 channels in control, after perfusion with MβCD, with EPA and after washout the cells with EPA-free external solution. (B) Current-voltage relationships under all conditions shown in (A). (C) Plot showing the voltage dependence of the MβCD and EPA effects (D) Activation curves and (E) normalized activation curves. Moreno et al. (2015).

Mentions: Moreno et al. (2015) analyzed the effects EPA and DHA in KV7.1/KCNE1 channels expressed on a heterologous expression system and in IKs in guinea pig myocytes. Two aspects of PUFA-dependent modulation of ion channels merit particular attention. (i) Dietary PUFAs incorporate to the cell membrane. Therefore, PUFAs-dependent modulation of ion channel depend on the way of administration: acute vs. chronic [see Moreno et al. (2012) for extensive review]. In fact, Moreno and colleagues reported that acute but not chronic administration of PUFAs increased the magnitude of KV7.1/KCNE1 channels and shifted the activation curve toward opposite directions (leftward and rightward shift for acute and chronic administration, respectively). In addition, long-term administration of n-3 PUFAs reduced KV7.1 but not KCNE1 expression due to increased degradation via proteasome. The significant decrease in KV7.1 expression level might account for the lack of current density increase when n-3 PUFAs were applied chronically (Moreno et al., 2015). (ii) Direct vs. indirect effects. As previously mentioned, there were two trends of opinion to explain the mechanism of action by which PUFAs modify ion channels: direct interaction vs. alteration of the cell membrane fluidity. Evidences in favor of both type of modulation were found simultaneously in the study by Moreno et al. (2015). Chronic administration of EPA and DHA disrupted lipid rafts domains where KV7.1 channels are normally found (Balijepalli et al., 2007) delocalizing KV7.1 in the cell membrane. Lipid raft disruption can be mimicked within minutes by the acute application of methyl-β-cyclodextrin (MBCD). The application of MBCD increased the current magnitude of KV7.1/KCNE1 at potentials positive to +30 mV and shifted the activation curve toward positive potentials emphasizing the impact of the membrane environment on channel properties (indirect effect; Figure 4; Moreno et al., 2015). On the other hand, after lipid raft disruption with MBCD, acute application of EPA produced similar effects than those observed in non-cholesterol-depleted cells: Current density increase and shift of the midpoint in the hyperpolarizing direction. This fast modulation was explained by a direct effect on the ion channel of EPA during acute application. Together these data provided evidence for direct and indirect PUFA dependent modulation of K+ channels suggesting that both mechanisms are not mutually exclusive and can happen simultaneously (Moreno et al., 2015).


In-Depth Study of the Interaction, Sensitivity, and Gating Modulation by PUFAs on K + Channels; Interaction and New Targets
Effects of EPA in membrane cholesterol-depleted cells with methyl-β-cyclodextrin (MβCD). (A) Current records obtained from the same cell and generated by KV7.1-KCNE1 channels in control, after perfusion with MβCD, with EPA and after washout the cells with EPA-free external solution. (B) Current-voltage relationships under all conditions shown in (A). (C) Plot showing the voltage dependence of the MβCD and EPA effects (D) Activation curves and (E) normalized activation curves. Moreno et al. (2015).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121229&req=5

Figure 4: Effects of EPA in membrane cholesterol-depleted cells with methyl-β-cyclodextrin (MβCD). (A) Current records obtained from the same cell and generated by KV7.1-KCNE1 channels in control, after perfusion with MβCD, with EPA and after washout the cells with EPA-free external solution. (B) Current-voltage relationships under all conditions shown in (A). (C) Plot showing the voltage dependence of the MβCD and EPA effects (D) Activation curves and (E) normalized activation curves. Moreno et al. (2015).
Mentions: Moreno et al. (2015) analyzed the effects EPA and DHA in KV7.1/KCNE1 channels expressed on a heterologous expression system and in IKs in guinea pig myocytes. Two aspects of PUFA-dependent modulation of ion channels merit particular attention. (i) Dietary PUFAs incorporate to the cell membrane. Therefore, PUFAs-dependent modulation of ion channel depend on the way of administration: acute vs. chronic [see Moreno et al. (2012) for extensive review]. In fact, Moreno and colleagues reported that acute but not chronic administration of PUFAs increased the magnitude of KV7.1/KCNE1 channels and shifted the activation curve toward opposite directions (leftward and rightward shift for acute and chronic administration, respectively). In addition, long-term administration of n-3 PUFAs reduced KV7.1 but not KCNE1 expression due to increased degradation via proteasome. The significant decrease in KV7.1 expression level might account for the lack of current density increase when n-3 PUFAs were applied chronically (Moreno et al., 2015). (ii) Direct vs. indirect effects. As previously mentioned, there were two trends of opinion to explain the mechanism of action by which PUFAs modify ion channels: direct interaction vs. alteration of the cell membrane fluidity. Evidences in favor of both type of modulation were found simultaneously in the study by Moreno et al. (2015). Chronic administration of EPA and DHA disrupted lipid rafts domains where KV7.1 channels are normally found (Balijepalli et al., 2007) delocalizing KV7.1 in the cell membrane. Lipid raft disruption can be mimicked within minutes by the acute application of methyl-β-cyclodextrin (MBCD). The application of MBCD increased the current magnitude of KV7.1/KCNE1 at potentials positive to +30 mV and shifted the activation curve toward positive potentials emphasizing the impact of the membrane environment on channel properties (indirect effect; Figure 4; Moreno et al., 2015). On the other hand, after lipid raft disruption with MBCD, acute application of EPA produced similar effects than those observed in non-cholesterol-depleted cells: Current density increase and shift of the midpoint in the hyperpolarizing direction. This fast modulation was explained by a direct effect on the ion channel of EPA during acute application. Together these data provided evidence for direct and indirect PUFA dependent modulation of K+ channels suggesting that both mechanisms are not mutually exclusive and can happen simultaneously (Moreno et al., 2015).

View Article: PubMed Central - PubMed

ABSTRACT

Voltage gated potassium channels (KV) are membrane proteins that allow selective flow of K+ ions in a voltage-dependent manner. These channels play an important role in several excitable cells as neurons, cardiomyocytes, and vascular smooth muscle. Over the last 20 years, it has been shown that omega-3 polyunsaturated fatty acids (PUFAs) enhance or decrease the activity of several cardiac KV channels. PUFAs-dependent modulation of potassium ion channels has been reported to be cardioprotective. However, the precise cellular mechanism underlying the cardiovascular benefits remained unclear in part because new PUFAs targets and signaling pathways continue being discovered. In this review, we will focus on recent data available concerning the following aspects of the KV channel modulation by PUFAs: (i) the exact residues involved in PUFAs-KV channels interaction; (ii) the structural PUFAs determinants important for their effects on KV channels; (iii) the mechanism of the gating modulation of KV channels and, finally, (iv) the PUFAs modulation of a few new targets present in smooth muscle cells (SMC), KCa1.1, K2P, and KATP channels, involved in vascular relaxation.

No MeSH data available.


Related in: MedlinePlus