Selective Small Molecule Activators of TREK-2 Channels Stimulate Dorsal Root Ganglion c-Fiber Nociceptor Two-Pore-Domain Potassium Channel Currents and Limit Calcium Influx.

ABSTRACT: The two-pore-domain potassium (K2P) channel TREK-2 serves to modulate plasma membrane potential in dorsal root ganglia c-fiber nociceptors, which tunes electrical excitability and nociception. Thus, TREK-2 channels are considered a potential therapeutic target for treating pain; however, there are currently no selective pharmacological tools for TREK-2 channels. Here we report the identification of the first TREK-2 selective activators using a high-throughput fluorescence-based thallium (Tl⁺) flux screen (HTS). An initial pilot screen with a bioactive lipid library identified 11-deoxy prostaglandin F2α as a potent activator of TREK-2 channels (EC₅₀ ≈ 0.294 μM), which was utilized to optimize the TREK-2 Tl⁺ flux assay (Z' = 0.752). A HTS was then performed w

SUBMITTER: Dadi PK 

PROVIDER: S-EPMC5901755 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature