title: Identification of novel small molecule modulators of K2P18.1 two-pore potassium channel.
abstract: 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±0.23 µM 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.
authors: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, Baltimore, MD 21205, USA.
authors: J Kyle
authors: JK
authors: Bruner
authors: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Beiyan
authors: B
authors: Zou
authors: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Hongkang
authors: H
authors: Zhang
authors: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Yixin
authors: Y
authors: Zhang
authors: Department of Physiology, Johns Hopkins University, Baltimore, MD 21205, USA.
authors: Katharina
authors: K
authors: Schmidt
authors: The Solomon H. Snyder Department of Neuroscience, High Throughput Biology Center, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Ion Channel Center (JHICC), Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: min.x.li@gsk.com.
authors: Min
authors: M
authors: Li
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D015221:Potassium Channels / Q000819:agonists / Q000235:genetics / Q000502:physiology*
chemical_list: C476574:KCNK18 protein, human; D049990:Membrane Transport Modulators; D015221:Potassium Channels
keywords: High-throughput screens; Ion channels; K(2P)18.1; Lidocaine (Pubchem CID 3676); Loratadine (Pubchem CID 3957); Small molecule drugs; Two-pore potassium channel