Bagriantsev, Sviatoslav N.; Ang, Kean-Hooi; Gallardo-Godoy, Alejandra; Clark, Kimberly A.; Arkin, Michelle R.; Renslo, Adam R.; Minor, Daniel L. published the artcile< A High-Throughput Functional Screen Identifies Small Molecule Regulators of Temperature- and Mechano-Sensitive K2P Channels>, Category: esters-buliding-blocks, the main research area is screening small mol temperature K2P potassium channel yeast.
K2P (KCNK) potassium channels generate “”leak”” potassium currents that strongly influence cellular excitability and contribute to pain, somatosensation, anesthesia, and mood. Despite their physiol. importance, K2Ps lack specific pharmacol. Addressing this issue has been complicated by the challenges that the leak nature of K2P currents poses for electrophysiol.-based high-throughput screening strategies. Here, we present a yeast-based high-throughput screening assay that avoids this problem. Using a simple growth-based functional readout, we screened a library of 106,281 small mols. and identified two new inhibitors and three new activators of the mammalian K2P channel K2P2.1 (KCNK2, TREK-1). By combining biophys., structure-activity, and mechanistic anal., we developed a dihydroacridine analog, ML67-33, that acts as a low micromolar, selective activator of temperature- and mechano-sensitive K2P channels. Biophys. studies show that ML67-33 reversibly increases channel currents by activating the extracellular selectivity filter-based C-type gate that forms the core gating apparatus on which a variety of diverse modulatory inputs converge. The new K2P modulators presented here, together with the yeast-based assay, should enable both mechanistic and physiol. studies of K2P activity and facilitate the discovery and development of other K2P small mol. modulators.
ACS Chemical Biology published new progress about Biological ion transport, potassium. 112-63-0 belongs to class esters-buliding-blocks, and the molecular formula is C19H34O2, Category: esters-buliding-blocks.
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