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To dislodge an enzyme from an ion channel, try steroids

Nature Chemical Biology volume 4, pages 650–651 (2008)Cite this article

Voltage-gated K+ channels assemble into complexes with Kvβs, a group of aldoketoreductases. The Kvβs regulate channel gating and localization, and voltage-dependent changes in the channel regulate AKR activity. Pan and colleagues now propose a new type of modulation of this complex. Cortisone disrupts the complex and relieves channel inactivation—which should reduce neuronal excitability.

How many things can one protein do, and how do you make it stop? For a class of auxiliary subunits of a K+ channel, Kvβs, the answers are “many” and “steroids”1. Kv1 channels shape neuronal action potentials and regulate lymphocytes2. Kvβs both regulate and are regulated by Kv1s, making them attractive research targets. The Kvβs govern channel localization, serving both as chaperones that enhance delivery to the plasma membrane3,4 and as targeting signals that direct channels to axons5. They also control channel conductance through the classic 'ball and chain' mechanism whereby a cytoplasmic peptide at the N terminus, like one found within the structure of some variants of the Kv1 channel itself, rapidly blocks the channel from the inside shortly after the channel has opened6. In addition to the ball and chain, which is found in some but not all of the Kvβs, they all have in common a highly conserved core domain of ∼330 amino acids. This core domain functions as an aldoketoreductase (AKR) and, like other AKRs, has a tightly bound NADPH cofactor at the active site7,8. Interestingly, both the enzymatic activity and the regulation of gating depend on NADPH. This common dependence may reflect an effect of a catalytic product on the channel or an allosteric effect on Kvβ structure of NADPH binding and a secondary allosteric effect on the structure of the channel. Either way, the coupling provides a potentially important link between a cell's internal metabolic state and the channel's regulation of membrane voltage. Equally noteworthy is the observation that the coupling is a two-way street. The enzyme's activity turns out to be voltage dependent9 —a consequence, it seems likely, of an allosteric influence of the gating rearrangements of the channel on the structure of the enzyme.

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Figure 1: Cortisone inserts between Kvβ and the Kv1 channel and disrupts their association.

References

  1. Pan, Y. et al. Nat. Chem. Biol. 6, 708–714 (2008).

    Article  Google Scholar 

  2. Hille, B. Ion Channels of Excitable Membranes 3rd edn., 131–160 (Sinauer, Sunderland, Massachusetts, 2001).

    Google Scholar 

  3. Shi, G. et al. Neuron 16, 843–852 (1996).

    Article  CAS  Google Scholar 

  4. Accili, E.A. et al. J. Physiol. (Lond.) 512, 325–336 (1998).

    Article  CAS  Google Scholar 

  5. Gu, C. et al. Science 301, 646–649 (2003).

    Article  CAS  Google Scholar 

  6. Rettig, J. et al. Nature 369, 289–294 (1994).

    Article  CAS  Google Scholar 

  7. Gulbis, J.M. et al. Cell 97, 943–952 (1999).

    Article  CAS  Google Scholar 

  8. Weng, J. et al. J. Biol. Chem. 281, 15194–15200 (2006).

    Article  CAS  Google Scholar 

  9. Pan, Y. et al. J. Biol. Chem. 283, 8634–8642 (2008).

    Article  CAS  Google Scholar 

  10. Long, S.B. et al. Science 309, 897–903 (2005).

    Article  CAS  Google Scholar 

  11. Gulbis, J.M. et al. Science 289, 123–127 (2000).

    Article  CAS  Google Scholar 

  12. Price, M. et al. Proc. Natl. Acad. Sci. USA 86, 10171–10175 (1989).

    Article  CAS  Google Scholar 

  13. McCormack, T. et al. J. Biol. Chem. 274, 20123–20126 (1999).

    Article  CAS  Google Scholar 

Download references

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  1. Susy C. Kohout and Ehud Y. Isacoff are in the Department of Molecular and Cell Biology, and Divisions of Material and Physical Bioscience, University of California, Berkeley, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ehud@berkeley.edu,

    Susy C Kohout & Ehud Y Isacoff

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  1. Susy C Kohout
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  2. Ehud Y Isacoff
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Kohout, S., Isacoff, E. To dislodge an enzyme from an ion channel, try steroids. Nat Chem Biol 4, 650–651 (2008). https://doi.org/10.1038/nchembio1108-650

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