Polyunsaturated Fatty Acids as Modulators of KV7 Channels

Abstract

Voltage-gated potassium channels of the K_V7 family are expressed in many tissues. The physiological importance of K_V7 channels is evident from specific forms of disorders linked to dysfunctional K_V7 channels, including variants of epilepsy, cardiac arrhythmia and hearing impairment. Thus, understanding how K_V7 channels are regulated in the body is of great interest. This Mini Review focuses on the effects of polyunsaturated fatty acids (PUFAs) on K_V7 channel activity and possible underlying mechanisms of action. By summarizing reported effects of PUFAs on K_V7 channels and native K_V7-mediated currents, we conclude that the generally observed effect is a PUFA-induced increase in current amplitude. The increase in current is commonly associated with a shift in the voltage-dependence of channel opening and in some cases with increased maximum conductance. Auxiliary KCNE subunits, which associate with K_V7 channels in certain tissues, may influence PUFA effects, though findings are conflicting. Both direct and indirect activating PUFA effects have been described, direct effects having been most extensively studied on K_V7.1. The negative charge of the PUFA head-group has been identified as critical for electrostatic interaction with conserved positively charged amino acids in transmembrane segments 4 and 6. Additionally, the localization of double bonds in the PUFA tail tunes the apparent affinity of PUFAs to K_V7.1. Indirect effects include those mediated by PUFA metabolites. Indirect inhibitory effects involve K_V7 channel degradation and re-distribution from lipid rafts. Understanding how PUFAs regulate K_V7 channels may provide insight into physiological regulation of K_V7 channels and bring forth new therapeutic strategies.

Keywords: KCNE; KCNQ; KV7; docosahexaenoic acid; lipid; polyunsaturated fatty acid; voltage-gated potassium channel.

FIGURE 1

Overview of K_V7 channel and PUFA molecular structures, and typified PUFA effects. (A) Schematic overview of K_V7 subtype expression and functional role. Note that these are examples, as some K_V7 subtypes have widespread expression and function. (B) Top view of K_V7.1 (PDB: 5VMS) with central pore domain in gray and peripheral voltage-sensing domains in black. Putative localization of KCNE at one K_V7.1 channel subunit is indicated [each subunit may accommodate one KCNE subunit (Sun and MacKinnon, 2020)]. Experimentally identified positively charged residues important for PUFA effects in K_V7.1 (Liin et al., 2018) are highlighted in red. Sequence alignment of the S6 site (important for G_max effect) and S4 site (important for V₅₀ effect) of all K_V7 isoforms are provided along with a side view of relevant channel domain. (C) Structure of the PUFA DHA, which has a carboxyl head linked to a 22-carbon long aliphatic tail with six cis double bonds. Deprotonation of the carboxyl head occurs at pH exceeding the pKa of the head-group, this endows DHA with a single negative charge. (D) Schematic overview of PUFA effect on current amplitude (I_Amp), mid-point of the G(V) curve (V₅₀), and maximum conductance (G_max) on indicated K_V7 subtypes. Please refer to Table 1 for further details. nd denotes not determined.