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High-Resolution Structures of K+ Channels

Part of the Handbook of Experimental Pharmacology book series (HEP,volume 267)

Abstract

Potassium channels are present in every living cell and essential to setting up a stable, non-zero transmembrane electrostatic potential which manifests the off-equilibrium livelihood of the cell. They are involved in other cellular activities and regulation, such as the controlled release of hormones, the activation of T-cells for immune response, the firing of action potential in muscle cells and neurons, etc. Pharmacological reagents targeting potassium channels are important for treating various human diseases linked to dysfunction of the channels. High-resolution structures of these channels are very useful tools for delineating the detailed chemical basis underlying channel functions and for structure-based design and optimization of their pharmacological and pharmaceutical agents. Structural studies of potassium channels have revolutionized biophysical understandings of key concepts in the field – ion selectivity, conduction, channel gating, and modulation, making them multi-modality targets of pharmacological regulation. In this chapter, I will select a few high-resolution structures to illustrate key structural insights, proposed allostery behind channel functions, disagreements still open to debate, and channel–lipid interactions and co-evolution. The known structural consensus allows the inference of conserved molecular mechanisms shared among subfamilies of K+ channels and makes it possible to develop channel-specific pharmaceutical agents.

Keywords

  • Activation, deactivation, and inactivation
  • Co-evolution of channels and lipids
  • Energetics and allostery
  • Ligand-gated K+ channels
  • Lipid-dependent gating
  • Pharmacological regulators and small molecule compounds
  • Structure-based drug design
  • Voltage-gated K+ channels (Kv)

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  • DOI: 10.1007/164_2021_454
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Acknowledgements

The research programs in the Jiang laboratory over the past years have been supported by NIH (R21GM131231, R01GM111367, R01GM093271 & R01GM088745), AHA (12IRG9400019), CF Foundation (JIANG15G0), Welch Foundation (I-1684), CPRIT (RP120474) and intramural funds at UT Southwestern, the University of Florida and the Hauptman-Woodward Medical Research Institute. I am indebted to many colleagues in the ion channel field for their valuable suggestions and advice to my research programs. Due to space limitation, I had to omit a lot of valuable work by many colleagues. I apologize for such omission due to personal selection.

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The author claims no conflict of interest.

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Correspondence to Qiu-Xing Jiang .

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Jiang, QX. (2021). High-Resolution Structures of K+ Channels. In: Gamper, N., Wang, K. (eds) Pharmacology of Potassium Channels. Handbook of Experimental Pharmacology, vol 267. Springer, Cham. https://doi.org/10.1007/164_2021_454

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