Kidney disease-related polycystic-2 ion channel regulated by small molecules

What is it about?

Human gene PKD2 encodes a crucial protein known as polycystin-2 (PC2). Mutations within the PKD2 gene can lead to autosomal dominant polycystic kidney disease (ADPKD), one of the most prevalent genetic disorders in humans. PC2 belongs to a class of proteins termed transient receptor potential (TRP) ion channels, responsible for facilitating the movement of charged ions like sodium, potassium, and calcium into and out of cells. However, the mechanisms governing the activation and deactivation of PC2 remain largely elusive, posing a significant challenge to understanding its role in ADPKD. In this investigation, we explored how certain small molecules impact a specific mutated form of PC2 known as PC2_F604P, which exhibits enhanced functionality. While most of these molecules were found to inhibit PC2_F604P, two compounds, ML-SA1 and SF-51, displayed a dual effect. At low concentrations, they activated PC2_F604P, whereas at high concentrations, they inactive it. Through structural biology techniques and experiments involving modified proteins, we pinpointed two distinct binding sites where ML-SA1 interacts with PC2_F604P, resulting in either activation or deactivation of the channel.

Featured Image

Photo by Shrinath on Unsplash

Photo by Shrinath on Unsplash

Why is it important?

These findings give us new insights into how small molecules can control the activity of the PC2 channel. By understanding how these molecules work, scientists might be able to design new drugs that are more effective and specific in targeting PC2 channels, potentially helping people to find treatment for ADPKD in the future.