BPS2026 – Lipid regulation of the nociceptive ion channel TRPM3

Cholesterol is a major constituent of the plasma membrane, here it interacts with many ion channels and has been described to confer a net inhibitory effect. The nociceptive ion channel TRPM3 is involved in pain and heat sensation. In recent solved structures, it has been shown that cholesterol-like molecules are found in important agonist binding pockets. This led to the hypothesis that cholesterol may be competitive with channel agonists. Here, we use whole-cell electrophysiology on heterologous TRPM3 expressing 293-HEK cells to demonstrate that cholesterol not only inhibits channel activation but also appears to be competitive with the channel agonist pregnenolone sulphate. This work will hopefully precede a better understanding of how TRPM3 maintains the closed state in the physiological plasma membrane, which can later be leveraged for therapeutic avenues.