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Identification of novel small molecule modulators of K2P18.1 two-pore potassium channel.
Bruner, J Kyle; Zou, Beiyan; Zhang, Hongkang; Zhang, Yixin; Schmidt, Katharina; Li, Min.
Afiliación
  • Bruner JK; 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.
  • Zou B; 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.
  • Zhang H; 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.
  • Zhang Y; 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.
  • Schmidt K; Department of Physiology, Johns Hopkins University, Baltimore, MD 21205, USA.
  • Li M; 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.
Eur J Pharmacol ; 740: 603-10, 2014 Oct 05.
Article en En | MEDLINE | ID: mdl-24972239
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Canales de Potasio / Moduladores del Transporte de Membrana Tipo de estudio: Diagnostic_studies Idioma: En Revista: Eur J Pharmacol Año: 2014 Tipo del documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Canales de Potasio / Moduladores del Transporte de Membrana Tipo de estudio: Diagnostic_studies Idioma: En Revista: Eur J Pharmacol Año: 2014 Tipo del documento: Article