Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Modulation of A-type potassium channels by a family of calcium sensors

Abstract

In the brain and heart, rapidly inactivating (A-type) voltage-gated potassium (Kv) currents operate at subthreshold membrane potentials to control the excitability of neurons and cardiac myocytes1,2. Although pore-forming α-subunits of the Kv4, or Shal-related, channel family form A-type currents in heterologous cells3, these differ significantly from native A-type currents. Here we describe three Kv channel-interacting proteins (KChIPs) that bind to the cytoplasmic amino termini of Kv4 α-subunits. We find that expression of KChIP and Kv4 together reconstitutes several features of native A-type currents by modulating the density, inactivation kinetics and rate of recovery from inactivation of Kv4 channels in heterologous cells. All three KChIPs co-localize and co-immunoprecipitate with brain Kv4 α-subunits, and are thus integral components of native Kv4 channel complexes. The KChIPs have four EF-hand-like domains and bind calcium ions. As the activity and density of neuronal A-type currents tightly control responses to excitatory synaptic inputs, these KChIPs may regulate A-type currents, and hence neuronal excitability, in response to changes in intracellular calcium.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: YTH interaction and tissue expression of KChIPs1–3.
Figure 2: Sequence alignment of human KChIPs with members of the recoverin family of Ca2+-sensing proteins.
Figure 3: Immunolocalization of Kv4 and KChIP1 in COS-1 cells and rat brain. a–c, COS-1 cells were transiently transfected with KChIP1 cDNA alone (a), Kv4.2 alone (b) or KChIP1 and Kv4.2 (c).
Figure 4: KChIPs co-associate with Fu4 α-subunits.
Figure 5: KChIP1 alters the density and kinetics of Kv4.2 currents in CHO cells.

References

  1. Hoffman D. A., Magee J. C., Colbert C. M. & Johnston,, D. K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons. Nature 387, 869–875 (1997).

    ADS  Article  Google Scholar 

  2. Dixon, J. E. et al. Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. Circ. Res. 79, 659–668 (1996).

    CAS  Article  Google Scholar 

  3. Serôdio, P., Kentros, C. & Rudy, B. Identification of molecular components of A-type channels activating at subthreshold potentials. J. Neurophys. 72, 1516–1529 (1994).

    Article  Google Scholar 

  4. Hoffman, D. A., & Johnston, D. Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC. J. Neurosci. 18, 3521–3528 (1998).

    CAS  Article  Google Scholar 

  5. Sheng, M., Tsaur, M. L., Jan Y. N. & Jan, L. Y. Subcellular segregation of two A-type K+ channel proteins in rat central neurons. Neuron 9, 271–284 (1992).

    CAS  Article  Google Scholar 

  6. Serôdio, P., Vega-Saenz de Miera, E. & Rudy, B. Cloning of a novel component of A-type K+ channels operating at subthreshold potentials with unique expression in heart and brain. J. Neurophys. 75, 2174–2179 (1996).

    Article  Google Scholar 

  7. Song, W. J. et al. Somatodendritic depolarization-activated potassium currents in rat neostriatal cholinergic interneurons are predominantly of the A type and attributable to coexpression of Kv4.2 and Kv4.1 subunits. J. Neurosci. 18, 3124–3137 (1998).

    CAS  Article  Google Scholar 

  8. Fields, S. & Song, O. A novel genetic system to detect protein–protein interactions. Nature 340, 245–246 (1989).

    ADS  CAS  Article  Google Scholar 

  9. Nef, P. in Guidebook to the Calcium-Binding Proteins (ed. Celio, M. R.) 94–97 (Oxford Univ. Press, New York, 1996).

    Google Scholar 

  10. Pongs, O. et al. Frequenin—a novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system. Neuron 11, 15–28 (1993).

    CAS  Article  Google Scholar 

  11. Buxbaum, J. D. et al. Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nature Med. 4, 1177–1181 (1998).

    CAS  Article  Google Scholar 

  12. Carrion, A. M., Link, W. A., Ledo, F., Mellstrom, B. & Naranjo, J. R. DREAM is a Ca2+-regulated transcriptional repressor. Nature 398, 80–84 (1999).

    ADS  CAS  Article  Google Scholar 

  13. Pak, M. D. et al. mShal, a subfamily of A-type K+ channel cloned from mammalian brain. Proc. Natl Acad. Sci. USA 88, 4386–4390 (1991).

    ADS  CAS  Article  Google Scholar 

  14. Kobayashi, M., Takamatsu, K., Saitoh, S. & Noguchi, T. Myristoylation of hippocalcin is linked to its calcium-dependent membrane association properties. J. Biol. Chem. 268, 18898–18904 (1993).

    CAS  PubMed  Google Scholar 

  15. Linse, S. & Forsen,, S. in Advances in Second Messenger and Phosphoprotein Research (ed. Means, S.) 89–150 (Ravens, New York,1995).

    Google Scholar 

  16. Chabala, L. D., Bakry, N. & Covarrubias, M. Low molecular weight poly(A)+ mRNA species encode factors that modulate gating of a non-Shaker A-type K+ channel. J. Gen. Physiol. 102, 713–728 (1993).

    CAS  Article  Google Scholar 

  17. Rudy, B., Hoger, J. H., Lester, H. A. & Davidson, N. At least two mRNA species contribute to the properties of rat brain A-type potassium channels expressed in Xenopus oocytes. Neuron 1, 649–658 (1988).

    CAS  Article  Google Scholar 

  18. Finley, R. L. & Brent, R. Interaction mating reveals binary and ternary connections between Drosophila cell cycle regulators. Proc. Natl Acad. Sci. USA 91, 12980–12984 (1994).

    ADS  CAS  Article  Google Scholar 

  19. Rhodes, K. J. et al. Association and colocalization of the Kvβ1 and Kvβ2 β-subunits with Kv1 α-subunits in mammalian brain K+ channel complexes. J. Neurosci. 17, 8246–8258 (1997).

    CAS  Article  Google Scholar 

  20. Bowlby, M. R. & Levitan,, I. B. Block of cloned voltage-gated potassium channels by the second messenger diacylglycerol independent of protein kinase C. J. Neurophys. 73, 2221–2229 (1995).

    CAS  Article  Google Scholar 

  21. Thompson, J. D., Higgins, D. G. & Gibson, T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994).

    CAS  Article  Google Scholar 

  22. Bairoch, A. & Cox, J. A. EF-hand motifs in inositol phospholipid-specific phospholipase C. FEBS Lett. 269, 454–456 (1990).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank P. Chanda and W. Edris for generation and purification of the recombinant KChIP proteins; J. Wardwell-Swanson and S. Nawoschik for generating mammalian and oocyte expression constructs; L. Buchwalder for preparation of the anti-KChIP and anti-Kv4 mouse monoclonal antibodies; J. Tang, K. Maden and S. Dembski for help with the yeast two-hybrid screen; K. Young, Q. Wang, Y. M. Xie, T. Novak, C. Gimeno and P. Errada for technical advice; and J. Moyer, J. Barrett, M. Cockett, P. McGonigle, J. Lillie, R. Breitbart, K. Willis and P. DiStefano for support and encouragement.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenneth J. Rhodes.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

An, W., Bowlby, M., Betty, M. et al. Modulation of A-type potassium channels by a family of calcium sensors. Nature 403, 553–556 (2000). https://doi.org/10.1038/35000592

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35000592

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing