A family of hyperpolarization-activated mammalian cation channels


Pacemaker activity of spontaneously active neurons1,2,3 and heart cells4,5,6 is controlled by a depolarizing, mixed Na+/K+ current, named Ih (or If 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, Ih 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 Ih by a mechanism that is independent of protein phosphorylation, and which involves direct binding of the cyclic nucleotide to the channel that mediates Ih10,11,12,13. 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 Ih 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.

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Figure 1: Primary structure of HAC1–3.
Figure 2: Expression of HAC1–3 mRNA.
Figure 3: Electrophysiological properties of the expressed HAC1 channel measured in whole-cell voltage clamp.
Figure 4: Modulation of the HAC1 current by cyclic nucleotides and channel blockers.


  1. 1

    Pape, H.-C. Queer current and pacemaker: the hyperpolarizaiton-activated cation current in neurons. Annu. Rev. Physiol. 58, 299–327 (1996).

    CAS  Article  Google Scholar 

  2. 2

    Halliwell, J. V. & Adams, P. R. Voltage-clamp analysis of muscarinic excitation in hippocampal neurons. Brain Res. 250, 71–92 (1982).

    CAS  Article  Google Scholar 

  3. 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).

    CAS  Article  Google Scholar 

  4. 4

    DiFrancesco, D. Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol. 55, 455–472 (1993).

    CAS  Article  Google Scholar 

  5. 5

    Brown, H. F., DiFrancesco, D. & Noble, S. J. How does adrenaline accelerate the heart? Nature 280, 235–236 (1979).

    ADS  CAS  Article  Google Scholar 

  6. 6

    DiFrancesco, D. Anew interpretation of the pace-maker current in calf Purkinje fibres. J. Physiol. 314, 359–376 (1981).

    CAS  Article  Google Scholar 

  7. 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).

    CAS  Article  Google Scholar 

  8. 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).

    CAS  Article  Google Scholar 

  9. 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).

    CAS  Article  Google Scholar 

  10. 10

    DiFrancesco, D. & Tortora, P. Direct activation of cardiac pacemaker channels by intracellular AMP. Nature 351, 145–147 (1991).

    ADS  CAS  Article  Google Scholar 

  11. 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).

    ADS  CAS  Article  Google Scholar 

  12. 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).

    CAS  Article  Google Scholar 

  13. 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).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Zagotta, W. N. & Siegelbaum, S. A. Structure and function of cyclic nucleotide-gated channels. Annu. Rev. Neurosci. 19, 235–263 (1996).

    CAS  Article  Google Scholar 

  15. 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).

    ADS  CAS  Article  Google Scholar 

  16. 16

    Heginbotham, L., Lu, Z., Abramson, T. & MacKinnon, R. Mutations in the K+ channel signature sequence. Biophys. J. 66, 1061–1067 (1994).

    CAS  Article  Google Scholar 

  17. 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).

    ADS  CAS  Article  Google Scholar 

  18. 18

    Ho, W.-K., Brown, H. F. & Noble, D. High selectivity of the ifchannel to Na+ and K+ in rabbit isolated sinoatrial node cells. Pflugers Arch. 426, 68–74 (1994).

    CAS  Article  Google Scholar 

  19. 19

    Yu, H., Chang, F. & Cohen, I. S. Pacemaker current ifin adult canine cardiac ventricular myocytes. J. Physiol. 485, 469–483 (1995).

    CAS  Article  Google Scholar 

  20. 20

    Hille, B. Ionic Channels of Excitable Membranes (Sinauer Associates, Sunderland, MA, (1992).

    Google Scholar 

  21. 21

    Baker, K., Warren, K. S., Yellen, G. & Fishman, M. C. Defective “pacemaker” current (Ih) in a zebrafish mutant with a slow heart rate. Proc. Natl Acad. Sci. USA 94, 4554–4559 (1997).

    ADS  CAS  Article  Google Scholar 

  22. 22

    Pape, H.-C. & Mager, R. Nitric oxide controls oscillatory activity in thalamocortical neurons. Neuron 9, 441–448 (1992).

    CAS  Article  Google Scholar 

  23. 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).

    CAS  Article  Google Scholar 

  24. 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).

    CAS  Article  Google Scholar 

  25. 25

    DiFrancesco, D. & Mangoni, M. Modulation of single hyperpolarization-activated channels (if) by cAMP in the rabbit sino-atrial node. J. Physiol. 474, 473–482 (1994).

    CAS  Article  Google Scholar 

  26. 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).

    CAS  Article  Google Scholar 

  27. 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).

    CAS  Article  Google Scholar 

  28. 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).

    ADS  CAS  Article  Google Scholar 

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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.

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Correspondence to Martin Biel.

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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

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