Female sex hormone found to block THIK-1 channel

Scientists have discovered that a female sex hormone, 17β-estradiol, can block a specific type of potassium channel known as THIK-1. THIK-1 plays a crucial role in microglia and macrophages, which are immune cells in the brain. While previous research suggested that steroids, including estradiol, could influence various potassium channels, the impact of estradiol on THIK-1 was not previously understood.

In a study published in the journal PLOS One, researchers investigated the effects of estradiol on THIK-1 channels. They found that 17β-estradiol, at a concentration of 10 micromolar, significantly inhibited mouse THIK-1 channels by approximately 40%. To further understand how estradiol interacts with THIK-1, the team used computer simulations and genetic mutations.

They identified specific sites within the hormone's structure that are responsible for inhibiting the channel. These sites are located in a region called the "pond" above the Y-gate of the THIK-1 channel.

Mutations in the THIK-1 gene, such as F142A, V269A, and Y273A, were also found to reduce estradiol's inhibitory effect. These mutations correspond to residues in the upper cavity of the channel, indicating that the structure of this region is crucial for estradiol's inhibitory action. Remarkably, when the researchers studied a human version of the THIK-1 channel, they discovered that it could be inhibited by estradiol at an even lower concentration of 10 nanomolar, which is a biologically relevant level.

The findings suggest that estradiol's ability to inhibit THIK-1 channels might have important implications for both normal physiological processes and potential pathological conditions involving THIK-1 variants. The study provides valuable insights into the molecular mechanisms underlying this hormonal regulation of a key immune cell channel in the brain.