Actions and Mechanisms of Polyunsaturated Fatty Acids on Voltage-Gated Ion Channels

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 (NaV), potassium (KV), calcium (CaV), and proton (HV) channels, as well as calcium-activated potassium (KCa), and transient receptor potential (TRP) channels. Some effects of fatty acids appear to be channel specific, whereas others seem to be more general. Common features for the fatty acids to act on the ion channels are at least two double bonds in cis geometry and a charged carboxyl group. In total we identify and label five different sites for the PUFAs. PUFA site 1: The intracellular cavity. Binding of PUFA reduces the current, sometimes as a time-dependent block, inducing an apparent inactivation. PUFA site 2: The extracellular entrance to the pore. Binding leads to a block of the channel. PUFA site 3: The intracellular gate. Binding to this site can bend the gate open and increase the current. PUFA site 4: The interface between the extracellular leaflet of the lipid bilayer and the voltage-sensor domain. Binding to this site leads to an opening of the channel via an electrostatic attraction between the negatively charged PUFA and the positively charged voltage sensor. PUFA site 5: The interface between the extracellular leaflet of the lipid bilayer and the pore domain. Binding to this site affects slow inactivation. This mapping of functional PUFA sites can form the basis for physiological and pharmacological modifications of voltage-gated ion channels.

Molecular Mechanisms of Resin Acids and Their Derivatives on the Opening of a Potassium Channel

“…Ottosson, N. E., Silverå-Ejneby, M., Wu, X., Yazdi, S., Konradsson P., Lindahl, E., and Elinder, F. (2017) A drug pocket at the lipid bilayerpotassium channel interface. Manuscript…”

“…Naturally occurring PUFAs (Figure 7) have important physiological functions, and they act on most ion channels (Boland and Drzewiecki 2008, Elinder and Liin 2017. The beneficial effects of PUFAs on cardiac arrhythmia and epilepsy were described more than 30 years ago (McLennan et al 1985, Hock et al 1990, Billman et al 1994, Xiao and Li 1999, Spector 2001.…”

“…The beneficial effects of PUFAs on cardiac arrhythmia and epilepsy were described more than 30 years ago (McLennan et al 1985, Hock et al 1990, Billman et al 1994, Xiao and Li 1999, Spector 2001. PUFAs potency to regulate neuronal excitability has been suggested to origin from their ability to close sodium-and calcium channels (Vreugdenhil et al 1996, Tigerholm et al 2012 in addition to open potassium channels , Xu et al 2008, Börjesson et al 2010, Börjesson and Elinder 2011, Elinder and Liin 2017.…”

“…In an extensive review by Elinder and Liin (Elinder and Liin 2017), some effects of fatty acids on ion channels appear to be channel specific, whereas three seem to be shift will open the channel, and the shift of inactivation will close the channel. For Nav and Cav channels, the G(V) shifting effects by PUFAs seem larger on inactivation than activation, which is why PUFAs generally inhibit these channels.…”

“…In the review by Elinder and Liin (Elinder and Liin 2017), five VGIC binding sites were suggested, where one is between the extracellular leaflet of the lipid bilayer and S4 Elinder 2011, Yazdi et al 2016). Our research group has characterized the effects of PUFAs binding to this site at the Shaker Kv channel , Xu et al 2008, Börjesson et al 2010, Börjesson and Elinder 2011, Tigerholm et al 2012, Ottosson et al 2014, Yazdi et al 2016) and lately also at the Kv7 channels (Liin et al 2015.…”