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The Polysite Pharmacology of TREK K2P Channels

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Ion Channels in Biophysics and Physiology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1349))

Abstract

K2P (KCNK) potassium channels form “background” or “leak” currents that have critical roles in cell excitability control in the brain, cardiovascular system, and somatosensory neurons. Similar to many ion channel families, studies of K2Ps have been limited by poor pharmacology. Of six K2P subfamilies, the thermo- and mechanosensitive TREK subfamily comprising K2P2.1 (TREK-1), K2P4.1 (TRAAK), and K2P10.1 (TREK-2) are the first to have structures determined for each subfamily member. These structural studies have revealed key architectural features that underlie K2P function and have uncovered sites residing at every level of the channel structure with respect to the membrane where small molecules or lipids can control channel function. This polysite pharmacology within a relatively small (~70 kDa) ion channel comprises four structurally defined modulator binding sites that occur above (Keystone inhibitor site), at the level of (K2P modulator pocket), and below (Fenestration and Modulatory lipid sites) the C-type selectivity filter gate that is at the heart of K2P function. Uncovering this rich structural landscape provides the framework for understanding and developing subtype-selective modulators to probe K2P function that may provide leads for drugs for anesthesia, pain, arrhythmia, ischemia, and migraine.

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Acknowledgments

We thank F. C. Chatelain for comments on the manuscript and P. Deal for help with figure preparation. This work was supported by grant NIH-R01-MH093603 to D.L.M.

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Authors and Affiliations

  1. Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, US

    Lianne Pope & Daniel L. Minor Jr

  2. Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

    Daniel L. Minor Jr

  3. California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA, USA

    Daniel L. Minor Jr

  4. Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA, USA

    Daniel L. Minor Jr

  5. Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    Daniel L. Minor Jr

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  1. Lianne Pope
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  2. Daniel L. Minor Jr
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Correspondence to Daniel L. Minor Jr .

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  1. Shenzhen Bay Laboratory, Institute of Molecular Physiology / Virginia Commonwealth University School of Medicine, Shenzhen, Guangdong Province, China

    Lei Zhou

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Pope, L., Minor, D.L. (2021). The Polysite Pharmacology of TREK K2P Channels. In: Zhou, L. (eds) Ion Channels in Biophysics and Physiology. Advances in Experimental Medicine and Biology, vol 1349. Springer, Singapore. https://doi.org/10.1007/978-981-16-4254-8_4

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