Title: Fatty acids effects on TMEM16A channels: The long and short of it
Abstract:
Transmembrane protein 16A (TMEM16A) is a widely expressed calcium-activated chloride channel that regulates diverse processes including inflammation, coronary blood flow, and asthma. Despite the robust evidence establishing this channel is critical, little is known about how it’s regulated by signals other than calcium. Here, we sought to determine whether polyunsaturated fatty acids (PUFAs) regulate TMEM16A channel activity. PUFAs are lipids composed of a carboxylic acid with an aliphatic hydrocarbon that dynamically drive protein conformational rearrangements of other proteins and ion channels. Moreover, PUFAs have target processes mediated by TMEM16A including increasing the production of proinflammatory mediators. By applying various PUFAs to excised patches made fromXenopus laevis oocytes, a cell type that abundantly expresses TMEM16A, we tested how PUFAs with different structural properties alter TMEM16A conducted currents. Here we report that PUFAs inhibit TMEM16A channels. For example, we found that 10 µM alpha-linolenic acid applied to excised inside-out patches reduced TMEM16A currents by 53 ± 6% (N=5) and 10 µM arachidonic acid by 82 ± 2% (N=9). To determine whether this PUFAs mediated inhibition requires polyunsaturated bonds in the lipid tails, we also applied a structurally similar but non-saturated lipid stearic acid. At 10 µM, stearic acid inhibited only 9 ± 6% of the current (N=5). Both alpha-linolenic acid and stearic acid have the same head group and 18-carbon lipid tail, which includes three double bonds for alpha-linolenic acid and none for stearic acid. This suggests that the unsaturated bonds are important for targeting TMEM16A. Understanding the interaction between TMEM16A-PUFAs is significant because it will shed light on how these channels operate and are regulated in their native cells. Moreover, delineating how PUFAs alter TMEM16A activity may provide a mechanistic link revealing how diets rich in PUFAs beneficially impact many physiological processes.
Carlson Lab
Friday, October 13th, 2023
12:00PM
Langley A219B