AI Insight
This study demonstrates that the steroid hormone 17β-estradiol inhibits the THIK-1 potassium channel, which plays important roles in microglia and macrophages, with approximately 40% inhibition at an IC50 of 4.9 μM. Through mutational analysis and docking simulations, researchers identified that estradiol binds to specific residues within an upper cavity region of the channel called the "pond." Certain mutations outside this region unexpectedly enhanced the channel's sensitivity to estradiol and other steroids, responding to concentrations as low as 10 nM, similar to a naturally occurring human THIK-1 variant.
Why it matters
These findings reveal a mechanism by which estradiol can modulate immune cell function through THIK-1 channels and suggest that some individuals carrying THIK-1 genetic variants may have altered responses to physiological estradiol levels, potentially affecting immune function and inflammatory processes.
Understand the Science
by Michihiro Tateyama, Yoshihiro Kubo
A two-pore domain K+ (K2P) channel, THIK-1, plays important roles in microglia and macrophage. THIK-1 is known to be activated by arachidonic acid and G protein-coupled receptors and inhibited by anesthetics. Steroids, such as cholesterol, estradiol and progesterone, are known to modulate several K+ channels and they might be potential modulators of THIK-1. We examined the effects of steroids on THIK-1 and found that estradiol inhibits mouse THIK-1 by approximately 40% (IC50 = 4.9 ± 1.5 μM). Docking simulations of THIK-1 with estradiol indicated possible docking sites, which were further assessed by introducing an alanine mutation into a residue at or near these locations. The F142A, V269A, and Y273A mutations reduced the inhibitory effect of estradiol. These residues are situated within the upper cavity above the Y gate in THIK-1 (pond), suggesting that the pond conformation is essential for estradiol-mediated inhibition. Conversely, the F145A and F276A mutations, located outside this region, were inhibited by 10 nM estradiol and enhanced inhibition by estradiol, estrone, estriol, and progesterone, likely due to conformational changes that facilitate steroid inhibition. The mouse T237S mutation, which corresponds to the reported human THIK-1 variant, produced effects similar to those seen with the F145A and F276A mutations, but to a lesser degree. In summary, estradiol-mediated THIK-1 inhibition depends on residues located in the pond, which may have physiological or pathological significance for THIK-1 variants which are inhibited by low concentration of estradiol.
Source: Inhibitory effect of 17β-estradiol on the THIK-1 channel