Two distinct mechanisms for K_2P potassium channels regulation 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. The activity of K_2P channels affects numerous physiological processes such as cardiac function, pain perception, depression and neuroprotection. We studied the influence of monoterpenes (MTs) on human K_2P channels using the Xenopus laevis oocytes expression system. We found that all mechano-gated K_2P channels are activated by MTs. In K_2P2.1 (TREK-1) channels, we identified, within the carboxyl-terminal, a triple arginine residue motif (R344-346), an apparent PIP₂-binding site, that is essential for regulation by holding potential changes and important for regulation by monoterpenes. Furthermore, carvacrol and cinnamaldehyde robustly enhance currents of the alkaline-sensitive K_2P5.1 (up to a 17-fold increase in current). Other members of the K_2P potassium channels, K_2P17.1, K_2P18.1, but not K_2P16.1, were activated by various MTs as well. Conversely, the activity of members of the acid-sensitive (TASK) K_2P channels (K_2P3.1 and K_2P9.1) was rapidly decreasing by monoterpenes. We found that MTs selectively decrease the voltage-dependent portion of the current and that current inhibition was reduced with the elevation of external K⁺ concentration. These findings suggest that penetration of MTs into the outer leaflet of the membrane results in immediate changes at the selectivity filter of members of the TASK channel family. We suggest MTs as promising new tools for the study of K_2P channels in vitro as well as in vivo.