A regulatory domain in the K_2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes

Potassium K_2P (‘leak’) channels conduct current across the entire physiological voltage range and carry leak or ‘background’ currents that are, in part, time- and voltage-independent. K_2P2.1 channels (i.e., TREK-1, KCNK2) are highly expressed in excitable tissues, where they play a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report for the first time that human K_2P2.1 channel activity is regulated by monoterpenes (MTs). We found that cyclic, aromatic monoterpenes containing a phenol moiety, such as carvacrol, thymol and 4-IPP had the most profound effect on current flowing through the channel (up to a 6-fold increase). By performing sequential truncation of the carboxyl-terminal domain of the channel and testing the activity of several channel regulators, we identified two distinct regulatory domains within this portion of the protein. One domain, as previously reported, was needed for regulation by arachidonic acid, anionic phospholipids, and temperature changes. Within a second domain, a triple arginine residue motif (R344–346), an apparent PIP₂-binding site, was found to be essential for regulation by holding potential changes and important for regulation by monoterpenes.