@article {Vealemol.113.091199, author = {Emma L Veale and Ehab Al-Moubarak and Naina Bajaria and Kiyoyuki Omoto and Lishuang Cao and Stephen J Tucker and Edward B Stevens and Alistair Mathie}, title = {Influence of the N-terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels}, elocation-id = {mol.113.091199}, year = {2014}, doi = {10.1124/mol.113.091199}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {TREK1 potassium channels are members of the two pore domain (K2P) potassium channel family and contribute to background potassium conductances in many cell types where their activity can be regulated by a variety of physiological and pharmacological mediators. Fenamates such as FFA, MFA, NFA and diclofenac and the related experimental drug, BL-1249 enhance the activity of TREK1 currents and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N-terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared to the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations which affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K+-selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2014/02/07/mol.113.091199}, eprint = {https://molpharm.aspetjournals.org/content/early/2014/02/07/mol.113.091199.full.pdf}, journal = {Molecular Pharmacology} }