Abstract
Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are thus potential drug targets for treating diseases. Here, we identify N-(4-cholorphenyl)-N-(2-(3,4-dihydrosioquinolin-2(1H)-yl)-2-oxoethyl)methanesulfonamide (TKDC) as an inhibitor of the TREK subfamily, including TREK-1, TREK-2 and TRAAK channels. Using TKDC as a chemical probe, a study combining computations, mutagenesis and electrophysiology reveals a K2P allosteric ligand-binding site located in the extracellular cap of the channels. Molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions lead to blockage of the ion conductive pathway. Using virtual screening approach, we identify other inhibitors targeting the extracellular allosteric ligand-binding site of these channels. Overall, our results suggest that the allosteric site at the extracellular cap of the K2P channels might be a promising drug target for these membrane proteins.
Highlights
Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are potential drug targets for treating diseases
We identified TKDC as an inhibitor of TREK-1 from an in-house library of approximately 1000 small molecules developed over time
In the whole-cell voltage clamp experiments on Chinese hamster ovary (CHO) cells that were transiently transfected with TREK-1, pronounced decreases in current were generated by perfusion with 10 μM TKDC (Fig. 1b, c)
Summary
Two-pore domain potassium (K2P) channels generate leak currents that are responsible for the maintenance of the resting membrane potential, and they are potential drug targets for treating diseases. Fifteen two-pore domain potassium (K2P) channels have been identified in the human genome[1, 2] They contribute to the background leak currents responsible for the maintenance of the resting membrane potential. In the transmembrane domain formed by the M2-M4 helices, there are prominent fenestrations connecting the inner pore with the milieu of the membrane These fenestrations could be occupied by lipid acyl chains or small molecular ligands that project into the intracellular ion conducting pore, contributing to a non-conductive channel[15, 16, 18]. Our results suggest that the allosteric conformational transitions induced by the interaction of inhibitors with the extracellular cap of K2P channels may provide a molecular basis for the development of drugs targeting K2P channels
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