A family of hyperpolarization-activated mammalian cation channels (original) (raw)

Nature volume 393, pages 587–591 (1998)Cite this article

Abstract

Pacemaker activity of spontaneously active neurons1,2,3 and heart cells4,5,6 is controlled by a depolarizing, mixed Na+/K+ current, named _I_h (or _I_f in the sinoatrial node of the heart)1,4. This current is activated on hyperpolarization of the plasma membrane. In addition to depolarizing pacemaker cells, _I_h is involved in determining the resting membrane potential of neurons1,2 and provides a mechanism to limit hyperpolarizing currents in these cells7,8,9. Hormones and neurotransmitters that induce a rise in cyclic AMP levels increase _I_h by a mechanism that is independent of protein phosphorylation, and which involves direct binding of the cyclic nucleotide to the channel that mediates _I_h10,11,12,13. Here we report the molecular cloning and functional expression of the gene encoding a hyperpolarization-activated cation channel (HAC1) that is present in brain and heart. This channel exhibits the general properties of _I_h channels. We have also identified full-length sequences of two related channels, HAC2 and HAC3, that are specifically expressed in the brain, indicating the existence of a family of hyperpolarization-activated cation channels.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 51 print issues and online access

$199.00 per year

only $3.90 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

References

  1. Pape, H.-C. Queer current and pacemaker: the hyperpolarizaiton-activated cation current in neurons. Annu. Rev. Physiol. 58, 299–327 (1996).
    Article CAS Google Scholar
  2. Halliwell, J. V. & Adams, P. R. Voltage-clamp analysis of muscarinic excitation in hippocampal neurons. Brain Res. 250, 71–92 (1982).
    Article CAS Google Scholar
  3. McCormick, D. A. & Pape, H.-C. Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurons. J. Physiol. 431, 291–318 (1990).
    Article CAS Google Scholar
  4. DiFrancesco, D. Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol. 55, 455–472 (1993).
    Article CAS Google Scholar
  5. Brown, H. F., DiFrancesco, D. & Noble, S. J. How does adrenaline accelerate the heart? Nature 280, 235–236 (1979).
    Article ADS CAS Google Scholar
  6. DiFrancesco, D. Anew interpretation of the pace-maker current in calf Purkinje fibres. J. Physiol. 314, 359–376 (1981).
    Article CAS Google Scholar
  7. Solomon, J. S. & Nerbonne, J. M. Hyperpolarization-activated currents in isolated superior colliculus-projecting neurons from rat visual cortex. J. Physiol. 462, 393–420 (1993).
    Article CAS Google Scholar
  8. Mayer, M. L. & Westbrook, G. L. Avoltage-clamp analysis of inward (anomalous) rectification in mouse spinal sensory ganglion neurons. J. Physiol. 340, 19–45 (1983).
    Article CAS Google Scholar
  9. Bayliss, D. A., Viana, F., Bellingham, M. C. & Berger, A. J. Characteristics and postnatal development of a hyperpolarization-activated inward current in rat hypoglossal motoneurons in vitro. J. Neurophysiol. 71, 119–128 (1994).
    Article CAS Google Scholar
  10. DiFrancesco, D. & Tortora, P. Direct activation of cardiac pacemaker channels by intracellular AMP. Nature 351, 145–147 (1991).
    Article ADS CAS Google Scholar
  11. Pape, H.-C. & McCormick, D. A. Noradrenalin and serotonin selectively modulate thalamic burst firing by enhancing a hyperpolarization-activated cation current. Nature 340, 715–718 (1989).
    Article ADS CAS Google Scholar
  12. McCormick, D. A. & Pape, H.-C. Noradrenergic and serotonergic modulation of a hyperpolarization-activated cation current in thalamic relay neurons. J. Physiol. 431, 319–342 (1990).
    Article CAS Google Scholar
  13. Pedarzani, P. & Storm, J. F. Protein kinase A-independent modulation of ion channels in the brain by cyclic AMP. Proc. Natl Acad. Sci. USA 92, 11716–11720 (1995).
    Article ADS CAS Google Scholar
  14. Zagotta, W. N. & Siegelbaum, S. A. Structure and function of cyclic nucleotide-gated channels. Annu. Rev. Neurosci. 19, 235–263 (1996).
    Article CAS Google Scholar
  15. Biel, M.et al. Another member of the cyclic nucleotide-gated channels family, expressed in testis, kidney, and heart. Proc. Natl Acad. Sci. USA 91, 3505–3509 (1994).
    Article ADS CAS Google Scholar
  16. Heginbotham, L., Lu, Z., Abramson, T. & MacKinnon, R. Mutations in the K+ channel signature sequence. Biophys. J. 66, 1061–1067 (1994).
    Article CAS Google Scholar
  17. Santoro, B., Grant, S. G. N., Bartsch, D. & Kandel, E. R. Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to Eag and cyclic nucleotide-gated channels. Proc. Natl Acad. Sci. USA 94, 14815–14820 (1997).
    Article ADS CAS Google Scholar
  18. Ho, W.-K., Brown, H. F. & Noble, D. High selectivity of the _i_fchannel to Na+ and K+ in rabbit isolated sinoatrial node cells. Pflugers Arch. 426, 68–74 (1994).
    Article CAS Google Scholar
  19. Yu, H., Chang, F. & Cohen, I. S. Pacemaker current _i_fin adult canine cardiac ventricular myocytes. J. Physiol. 485, 469–483 (1995).
    Article CAS Google Scholar
  20. Hille, B. Ionic Channels of Excitable Membranes (Sinauer Associates, Sunderland, MA, (1992).
    Google Scholar
  21. Baker, K., Warren, K. S., Yellen, G. & Fishman, M. C. Defective “pacemaker” current (_I_h) in a zebrafish mutant with a slow heart rate. Proc. Natl Acad. Sci. USA 94, 4554–4559 (1997).
    Article ADS CAS Google Scholar
  22. Pape, H.-C. & Mager, R. Nitric oxide controls oscillatory activity in thalamocortical neurons. Neuron 9, 441–448 (1992).
    Article CAS Google Scholar
  23. Ludwig, A., Flockerzi, V. & Hofmann, F. Regional expression and cellular localization of the α1and β subunit of high voltage-activated calcium channels in rat brain. J. Neurosci. 17, 1339–1349 (1997).
    Article CAS Google Scholar
  24. Biel, M., Zong, X., Ludwig, A., Sautter, A. & Hofmann, F. Molecular cloning and expression of a modulatory subunit of the cyclic nucleotide-gated cation channel. J. Biol. Chem. 271, 6349–6355 (1996).
    Article CAS Google Scholar
  25. DiFrancesco, D. & Mangoni, M. Modulation of single hyperpolarization-activated channels (_i_f) by cAMP in the rabbit sino-atrial node. J. Physiol. 474, 473–482 (1994).
    Article CAS Google Scholar
  26. Titani, K.et al. Amino acid sequence of the regulatory subunit of bovine type I adenosine cyclic 3′,5′-phosphate dependent protein kinase. Biochemistry 23, 4193–4199 (1984).
    Article CAS Google Scholar
  27. Weber, I. T. & Steitz, T. A. Structure of a complex of catabolite gene activator protein and cyclic AMP refined at 2.5 Å. J. Mol. Biol. 198, 311–326 (1987).
    Article CAS Google Scholar
  28. Warmke, J. W. & Ganetzky, B. Afamily of potassium channel genes related to eag in Drosophila and mammals. Proc. Natl Acad. Sci. USA 91, 3438–3442 (1994).
    Article ADS CAS Google Scholar

Download references

Acknowledgements

We thank P. Mayr, B. Lehnert, S. Stief and S. Ehrhard for technical support. Research was supported by grants from Deutsche Forschungsgemeinschaft and Fond der Chemischen Industrie.

Author information

Authors and Affiliations

  1. Institut für Pharmakologie und Toxikologie, Technische Universität München, Biedersteiner Strasse 29, München, 80802, Germany
    Andreas Ludwig, Xiangang Zong, Michael Jeglitsch, Franz Hofmann & Martin Biel

Authors

  1. Andreas Ludwig
    You can also search for this author inPubMed Google Scholar
  2. Xiangang Zong
    You can also search for this author inPubMed Google Scholar
  3. Michael Jeglitsch
    You can also search for this author inPubMed Google Scholar
  4. Franz Hofmann
    You can also search for this author inPubMed Google Scholar
  5. Martin Biel
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toMartin Biel.

Rights and permissions

About this article

Cite this article

Ludwig, A., Zong, X., Jeglitsch, M. et al. A family of hyperpolarization-activated mammalian cation channels.Nature 393, 587–591 (1998). https://doi.org/10.1038/31255

Download citation

This article is cited by