Polyunsaturated Fatty Acids as Modulators of KV7 Channels

Abstract

Voltage-gated potassium channels of the K V 7 family are expressed in many tissues. The physiological importance of K V 7 channels is evident from specific forms of disorders linked to dysfunctional K V 7 channels, including variants of epilepsy, cardiac arrhythmia and hearing impairment. Thus, understanding how K V 7 channels are regulated in the body is of great interest. This Mini Review focuses on the effects of polyunsaturated fatty acids (PUFAs) on K V 7 channel activity and possible underlying mechanisms of action. By summarizing reported effects of PUFAs on K V 7 channels and native K V 7-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 V 7 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 V 7.1. 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 V 7.1. Indirect effects include those mediated by PUFA metabolites. Indirect inhibitory effects involve K V 7 channel degradation and redistribution from lipid rafts. Understanding how PUFAs regulate K V 7 channels may provide insight into physiological regulation of K V 7 channels and bring forth new therapeutic strategies.

Cannabidiol activates neuronal Kv7 channels

“…Our results add to recent experiments demonstrating that Kv7.2/7.3 channels are susceptible to enhancement by a wide variety of agents acting by several different mechanisms ( De Silva et al, 2018 ; Manville and Abbott, 2018c ; Manville and Abbott, 2018a ; Miceli et al, 2018 ; Wang et al, 2018 ; Kanyo et al, 2020 ; Kurata, 2020 ; Li et al, 2020 ). Such agents include endogenous compounds like GABA ( Manville et al, 2018b ), the ketone body β-hydroxybutyrate ( Manville et al, 2020 ), and arachidonic acid metabolites and derivatives ( Schweitzer et al, 1990 ; Schweitzer et al, 1993 ; Larsson et al, 2020a ; Larsson et al, 2020b ), as well as a variety of natural products including cilantro ( Manville and Abbott, 2019 ). Further development of Kv7.2/7.3 enhancers for treating epilepsy and other neuronal disorders seems promising ( Maljevic and Lerche, 2014 ; Vigil et al, 2020 ), especially because retigabine has been withdrawn from clinical use because of a number of off-target side effects ( Brickel et al, 2020 ).…”

Cannabidiol counters the effects of a dominant-negative pathogenic Kv7.2 variant

“…However, it is possible that CBD could interact with other receptors or channels in tsA-201 cells that could invoke other factors that modulate Kv7 channels (i.e. PiP2, PKC, calmodulin, arachidonic acid, and ERK1-2) ( Borgini et al., 2021 ; Greene and Hoshi, 2016 ; Hudson et al., 2019 ; Larsson et al., 2020a ).…”

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

“…Despite this, there is strong evidence that could support the initiation of future clinical trials, especially for auditory pathologies as well as in PD [ 14 , 80 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 ], and developments for understanding the effects that antimicrobial agents have on these potassium ion channels [ 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 ]. Additionally, the scope of this review was on neural modulation, yet there is a growing amount of literature on the behavior of KCNQ channels in cardiac modulations as well, especially in the cellular processes involved in arrhythmia [ 26 , 27 , 28 , 29 , 139 , 140 , 141 , 142 , 143 , 144 , 14...…”