Gating shift to an ohmic mode of TREK-1 channel induced by docosahexaenoic acid

The TREK-1 channel is a polymodulated K2P channel that responds to a wide range of physical and chemical stimuli, enabling it to contribute to the regulation of cellular excitability. This member of the TREK sub-family exhibits an outward rectification resulting from voltage-dependent gating, which can be reversibly converted to an ohmic leak mode by both synthetic and natural modulators. The present study aimed to investigate the gating mechanism in response to docosahexaenoic acid (DHA), using transient transfections of either the wild-type (WT) TREK-1 channel or its G171D variant at the transmembrane (TM)2.6 position in HEK 293T cells. We reported that DHA enhances the WT TREK-1 current by increasing the proportion of channels in a conductive state across the entire membrane potential (Vm) range, effectively shifting TREK-1 into an ohmic mode. Furthermore, we observed that disrupting the C-type gate function blunted DHA-induced activation, suggesting that DHA acts by stabilizing the selectivity filter that may involve TM2. Additionally, we observed considerable variability in the initial activity of TREK-1 under control conditions, which accounts for the heterogeneous effects of DHA among cells. These findings highlight the complex gating mechanism of TREK-1 and reveal a dynamic mechanism by which DHA, and likely other polyunsaturated fatty acids (PUFAs), modulate Vm and influence cellular excitability.