Identification of novel small molecule modulators of K2P18.1 two-pore potassium channel

• Published in: European journal of pharmacology 2014-10, Vol.740, p.603-610
• Main Authors: Bruner, J. Kyle, Zou, Beiyan, Zhang, Hongkang, Zhang, Yixin, Schmidt, Katharina, Li, Min
• Format: Article
• Language: English
• Subjects: HEK293 Cells; High-throughput screens; Humans; Ion channels; K2P18.1; Membrane Potentials - drug effects; Membrane Transport Modulators - pharmacology; Mutagenesis, Site-Directed; Potassium Channels - agonists; Potassium Channels - genetics; Potassium Channels - physiology; Small molecule drugs; Two-pore potassium channel
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2014.06.021

Two-pore domain potassium (K2P) channels are responsible for background potassium (K+) current, which is crucial for the maintenance of resting membrane potential. K2P18.1, also called TWIK-related spinal cord K+ channel (TRESK) or KCNK18, is thought to be a major contributor to background K+ currents, particularly in sensory neurons where it is abundantly expressed. Despite its critical role and potential therapeutic implication, pharmacological tools for probing K2P18.1 activity remain unavailable. Here, we report a high-throughput screen against a collection of bioactive compounds that yielded 26 inhibitors and 8 activators of K2P18.1 channel activity with more than 10-fold selectivity over the homologous channel K2P9.1. Among these modulators, the antihistamine loratadine inhibited K2P18.1 activity with IC50 of 0.49±0.23µM and is considerably more potent than existing K2P18.1 inhibitors. Importantly, the inhibition by loratadine remains equally efficacious upon potentiation of K2P18.1 by calcium signaling. Furthermore, the loratadine effect is dependent on transmembrane residues F145 and F352, providing orthogonal evidence that the inhibition is caused by a direct compound–channel interaction. This study reveals new pharmacological modulators of K2P18.1 activity useful in dissecting native K2P18.1 function.