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Cortisone dissociates the Shaker family K+ channels from their β subunits

Nature Chemical Biology volume 4, pages 708–714 (2008)Cite this article

Abstract

The Shaker family voltage-dependent potassium channels (Kv1) are expressed in a wide variety of cells and are essential for cellular excitability. In humans, loss-of-function mutations of Kv1 channels lead to hyperexcitability and are directly linked to episodic ataxia and atrial fibrillation. All Kv1 channels assemble with β subunits (Kvβs), and certain Kvβs, for example Kvβ1, have an N-terminal segment that closes the channel by the N-type inactivation mechanism. In principle, dissociation of Kvβ1, although never reported, should eliminate inactivation and thus potentiate Kv1 current. We found that cortisone increases rat Kv1 channel activity by binding to Kvβ1. A crystal structure of the Kvβ-cortisone complex was solved to 1.82-Å resolution and revealed novel cortisone binding sites. Further studies demonstrated that cortisone promotes dissociation of Kvβ. The new mode of channel modulation may be explored by native or synthetic ligands to fine-tune cellular excitability.

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Figure 1: Cortisone potentiates Kv1.1 current via the AKR core of Kvβ.
Figure 2: Each Kvβ2 binds two cortisone molecules.
Figure 3: Binding to the enzymatic site is not required for channel modulation.
Figure 4: Binding to the interface site modulates channel inactivation.
Figure 5: Cortisone promotes dissociation of Kvβ.

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Acknowledgements

We thank R. MacKinnon (Rockefeller University) for advice and generous help throughout the project. We thank C. Deutsch (University of Pennsylvania) and C. Miller (Brandeis University) for critical comments on the manuscript. Data for this study were measured at beamlines X4A, X4C and X29 of the National Synchrotron Light Source. We thank J. Schwanof, R. Abramowitz, S. Myers, N. Whalen and R. Jackimowicz for technical support during data collection. This work was supported by the American Heart Association (0630148N to M.Z. and 0826067D to Y.P.), the US National Institutes of Health (HL086392 to M.Z.), the March of Dimes Birth Defects Foundation (research grant #5-FY06-20 to M.Z.) and a grant from the Pew Scholars Program (to M.Z.).

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  1. Yaping Pan and Jun Weng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, 10032, New York, USA

    Yaping Pan, Jun Weng, Venkataraman Kabaleeswaran, Huiguang Li, Yu Cao, Rahul C Bhosle & Ming Zhou

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  1. Yaping Pan
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Correspondence to Ming Zhou.

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Supplementary Figures 1–3, Supplementary Table 1 and Supplementary Methods (PDF 229 kb)

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Pan, Y., Weng, J., Kabaleeswaran, V. et al. Cortisone dissociates the Shaker family K+ channels from their β subunits. Nat Chem Biol 4, 708–714 (2008). https://doi.org/10.1038/nchembio.114

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