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  • Review Article
  • Published:

Exploring HCN channels as novel drug targets

Key Points

  • Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated ion channel superfamily that are dually gated by membrane hyperpolarization and cyclic nucleotides. The current produced by HCN channels is called Ih (hyperpolarization-activated current) or If (funny current).

  • HCN channels have a key role in controlling cardiac pacemaker activity and are important regulators of neuronal excitability. Dysfunction of HCN channels has been implicated in arrhythmogenic diseases of the heart and several diseases of the nervous system, including pain disorders, epilepsy and ataxia.

  • Ivabradine is the first HCN channel blocker that has been clinically approved. Ivabradine efficiently lowers heart rate by blocking the sinoatrial HCN4 channel, and is used for the treatment of stable angina pectoris.

  • HCN1 and HCN2 channels are involved in the pathologies of inflammatory and neuropathic pain disorders. Compounds acting on these two channels are promising candidates for treating peripheral pain modalities.

  • Compounds acting on HCN1 and HCN2 channels might be also valuable in other indications such as anaesthesia and the treatment of various types of epilepsies.

  • The design of agents that selectively target each of the four HCN channel isoforms is an important goal for future drug development. To avoid side effects on cardiac rhythmicity, compounds targeting the central nervous system should have a low affinity for the sinoatrial HCN4 channel.

  • A first series of subtype-selective HCN channel compounds has been developed based on the ivabradine backbone. Other compounds acting on HCN channels (for example, clonidine or nicotine) may serve as alternative lead structures for the development of next-generation drugs targeting HCN channels.

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have a key role in the control of heart rate and neuronal excitability. Ivabradine is the first compound acting on HCN channels to be clinically approved for the treatment of angina pectoris. HCN channels may offer excellent opportunities for the development of novel anticonvulsant, anaesthetic and analgesic drugs. In support of this idea, some well-established drugs that act on the central nervous system — including lamotrigine, gabapentin and propofol — have been found to modulate HCN channel function. This Review gives an up-to-date summary of compounds acting on HCN channels, and discusses strategies to further explore the potential of these channels for therapeutic intervention.

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Figure 1: HCN channels: phylogenetic tree and transmembrane topology.
Figure 2: Functional properties of HCN channel currents.
Figure 3: Mechanism of action of ivabradine on sinoatrial HCN channels.
Figure 4: Structures of compounds interacting with hyperpolarization-activated cyclic nucleotide-gated channels.
Figure 5: Development of derivatives of ivabradine with increased subtype specificity.

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References

  1. Biel, M., Wahl-Schott, C., Michalakis, S. & Zong, X. Hyperpolarization-activated cation channels: from genes to function. Physiol. Rev. 89, 847–885 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Robinson, R. B. & Siegelbaum, S. A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol. 65, 453–480 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Baruscotti, M., Bucchi, A. & Difrancesco, D. Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacol. Ther. 107, 59–79 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Noam, Y., Bernard, C. & Baram, T. Z. Towards an integrated view of HCN channel role in epilepsy. Curr. Opin. Neurobiol. 20 Jun 2011 (doi:10.1016/j.conb.2011.06.013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lewis, A. S. & Chetkovich, D. M. HCN channels in behavior and neurological disease: too hyper or not active enough? Mol. Cell. Neurosci. 46, 357–367 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Dunlop, J., Vasilyev, D., Lu, P., Cummons, T. & Bowlby, M. R. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and pain. Curr. Pharm. Des. 15, 1767–1772 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Yu, F. H., Yarov-Yarovoy, V., Gutman, G. A. & Catterall, W. A. Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol. Rev. 57, 387–395 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Gauss, R., Seifert, R. & Kaupp, U. B. Molecular identification of a hyperpolarization-activated channel in sea urchin sperm. Nature 393, 583–587 (1998). This was the first study to report the cloning of an invertebrate HCN channel.

    Article  CAS  PubMed  Google Scholar 

  12. Ishii, T. M., Takano, M., Xie, L. H., Noma, A. & Ohmori, H. Molecular characterization of the hyperpolarization-activated cation channel in rabbit heart sinoatrial node. J. Biol. Chem. 274, 12835–12839 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Krieger, J., Strobel, J., Vogl, A., Hanke, W. & Breer, H. Identification of a cyclic nucleotide- and voltage-activated ion channel from insect antennae. Insect Biochem. Mol. Biol. 29, 255–267 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Ludwig, A., Zong, X., Jeglitsch, M., Hofmann, F. & Biel, M. A family of hyperpolarization-activated mammalian cation channels. Nature 393, 587–591 (1998). This was the first study to identify three members of the HCN channel family in a mouse brain.

    Article  CAS  PubMed  Google Scholar 

  15. Ludwig, A. et al. Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J. 18, 2323–2329 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Marx, T., Gisselmann, G., Stortkuhl, K. F., Hovemann, B. T. & Hatt, H. Molecular cloning of a putative voltage- and cyclic nucleotide-gated ion channel present in the antennae and eyes of Drosophila melanogaster. Invert. Neurosci. 4, 55–63 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Seifert, R. et al. Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc. Natl Acad. Sci. USA 96, 9391–9396 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Santoro, B. et al. Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93, 717–729 (1998). This was the first study to report the cloning and functional expression of HCN1.

    Article  CAS  PubMed  Google Scholar 

  19. Santoro, B., Grant, S. G., 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  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shi, W. et al. Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ. Res. 85, e1–e6 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Mannikko, R., Elinder, F. & Larsson, H. P. Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages. Nature 419, 837–841 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Zagotta, W. N. et al. Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425, 200–205 (2003). This study reported the crystal structure of the CNBD–C-linker of HCN2.

    Article  CAS  PubMed  Google Scholar 

  23. Xu, X., Vysotskaya, Z. V., Liu, Q. & Zhou, L. Structural basis for the cAMP-dependent gating in the human HCN4 channel. J. Biol. Chem. 285, 37082–37091 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Wainger, B. J., DeGennaro, M., Santoro, B., Siegelbaum, S. A. & Tibbs, G. R. Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature 411, 805–810 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Mistrik, P. et al. The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. J. Biol. Chem. 280, 27056–27061 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Ulens, C. & Tytgat, J. Functional heteromerization of HCN1 and HCN2 pacemaker channels. J. Biol. Chem. 276, 6069–6072 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Moosmang, S., Biel, M., Hofmann, F. & Ludwig, A. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol. Chem. 380, 975–980 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Monteggia, L. M., Eisch, A. J., Tang, M. D., Kaczmarek, L. K. & Nestler, E. J. Cloning and localization of the hyperpolarization-activated cyclic nucleotide-gated channel family in rat brain. Brain Res. Mol. Brain Res. 81, 129–139 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Santoro, B. et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J. Neurosci. 20, 5264–5275 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Notomi, T. & Shigemoto, R. Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain. J. Comp. Neurol. 471, 241–276 (2004). This is an extensive immunohistochemistry study examining the expression pattern of all four HCN channels in the rat brain.

    Article  CAS  PubMed  Google Scholar 

  32. Moosmang, S. et al. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur. J. Biochem. 268, 1646–1652 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Fenske, S. et al. HCN3 contributes to the ventricular action potential waveform in the murine heart. Circ. Res. 109, 1015–1023 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Muller, F. et al. HCN channels are expressed differentially in retinal bipolar cells and concentrated at synaptic terminals. Eur. J. Neurosci. 17, 2084–2096 (2003).

    Article  PubMed  Google Scholar 

  35. Cho, H. J., Staikopoulos, V., Furness, J. B. & Jennings, E. A. Inflammation-induced increase in hyperpolarization-activated, cyclic nucleotide-gated channel protein in trigeminal ganglion neurons and the effect of buprenorphine. Neuroscience 162, 453–461 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Vasilyev, D. V. et al. Direct inhibition of Ih by analgesic loperamide in rat DRG neurons. J. Neurophysiol. 97, 3713–3721 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Tellez, J. O. et al. Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit. Circ. Res. 99, 1384–1393 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Liu, J., Dobrzynski, H., Yanni, J., Boyett, M. R. & Lei, M. Organisation of the mouse sinoatrial node: structure and expression of HCN channels. Cardiovasc. Res. 73, 729–738 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Stieber, J. et al. The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc. Natl Acad. Sci. USA 100, 15235–15240 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Baruscotti, M. et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc. Natl Acad. Sci. USA 108, 1705–1710 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ludwig, A. et al. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J. 22, 216–224 (2003). This report shows that deletion of HCN2 leads to absence epilepsy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cho, H. J., Furness, J. B. & Jennings, E. A. Post-natal maturation of the hyperpolarisation-activated cation current, Ih, in trigeminal sensory neurons. J. Neurophysiol. 106, 2045–2056 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Huang, X., Yang, P., Du, Y., Zhang, J. & Ma, A. Age-related down-regulation of HCN channels in rat sinoatrial node. Basic Res. Cardiol. 102, 429–435 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Surges, R. et al. Regulated expression of HCN channels and cAMP levels shape the properties of the h current in developing rat hippocampus. Eur. J. Neurosci. 24, 94–104 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zolles, G. et al. Association with the auxiliary subunit PEX5R/Trip8b controls responsiveness of HCN channels to cAMP and adrenergic stimulation. Neuron 62, 814–825 (2009). This was a proteomic study on neuronal HCN channel complexes.

    Article  CAS  PubMed  Google Scholar 

  46. Santoro, B. et al. TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 62, 802–813 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lewis, A. S. et al. Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function. J. Neurosci. 29, 6250–6265 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Piskorowski, R., Santoro, B. & Siegelbaum, S. A. TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron 70, 495–509 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lipscombe, D. & Pan, J. Q. Tripping the HCN breaker. Neuron 62, 747–750 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Yu, H. et al. MinK-related peptide 1: a β subunit for the HCN ion channel subunit family enhances expression and speeds activation. Circ. Res. 88, e84–e87 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Michels, G. et al. K+ channel regulator KCR1 suppresses heart rhythm by modulating the pacemaker current If . PLoS ONE 3, e1511 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gravante, B. et al. Interaction of the pacemaker channel HCN1 with filamin A. J. Biol. Chem. 279, 43847–43853 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Kimura, K., Kitano, J., Nakajima, Y. & Nakanishi, S. Hyperpolarization-activated, cyclic nucleotide-gated HCN2 cation channel forms a protein assembly with multiple neuronal scaffold proteins in distinct modes of protein–protein interaction. Genes Cells 9, 631–640 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Barbuti, A., Terragni, B., Brioschi, C. & DiFrancesco, D. Localization of f-channels to caveolae mediates specific β2-adrenergic receptor modulation of rate in sinoatrial myocytes. J. Mol. Cell. Cardiol. 42, 71–78 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Pian, P., Bucchi, A., Robinson, R. B. & Siegelbaum, S. A. Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2 . J. Gen. Physiol. 128, 593–604 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zolles, G. et al. Pacemaking by HCN channels requires interaction with phosphoinositides. Neuron 52, 1027–1036 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Fogle, K. J., Lyashchenko, A. K., Turbendian, H. K. & Tibbs, G. R. HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2. J. Neurosci. 27, 2802–2814 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Frace, A. M., Maruoka, F. & Noma, A. Control of the hyperpolarization-activated cation current by external anions in rabbit sino-atrial node cells. J. Physiol. 453, 307–318 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Munsch, T. & Pape, H. C. Modulation of the hyperpolarization-activated cation current of rat thalamic relay neurones by intracellular pH. J. Physiol. 519 (Pt 2), 493–504 (1999).

    Google Scholar 

  60. Zong, X., Stieber, J., Ludwig, A., Hofmann, F. & Biel, M. A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2. J. Biol. Chem. 276, 6313–6319 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Stevens, D. R. et al. Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature 413, 631–635 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Wahl-Schott, C., Baumann, L., Zong, X. & Biel, M. An arginine residue in the pore region is a key determinant of chloride dependence in cardiac pacemaker channels. J. Biol. Chem. 280, 13694–13700 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Zong, X. et al. A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase. J. Biol. Chem. 280, 34224–34232 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Arinsburg, S. S., Cohen, I. S. & Yu, H. G. Constitutively active Src tyrosine kinase changes gating of HCN4 channels through direct binding to the channel proteins. J. Cardiovasc. Pharmacol. 47, 578–586 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Poolos, N. P., Bullis, J. B. & Roth, M. K. Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase. J. Neurosci. 26, 7995–8003 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jung, S. et al. Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling. J. Neurosci. 30, 6678–6688 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hammelmann, V., Zong, X., Hofmann, F., Michalakis, S. & Biel, M. The cGMP-dependent protein kinase II is an inhibitory modulator of the hyperpolarization-activated HCN2 channel. PLoS ONE 6, e17078 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Baruscotti, M., Bottelli, G., Milanesi, R., DiFrancesco, J. C. & DiFrancesco, D. HCN-related channelopathies. Pflugers Arch. 460, 405–415 (2010). This paper provides an excellent overview of HCN channelopathies.

    Article  CAS  PubMed  Google Scholar 

  69. DiFrancesco, D. The role of the funny current in pacemaker activity. Circ. Res. 106, 434–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Cohen, I. S. & Robinson, R. B. Pacemaker current and automatic rhythms: toward a molecular understanding. Handb. Exp. Pharmacol. 171, 41–71 (2006).

    Article  Google Scholar 

  71. Jiang, Y. Q., Sun, Q., Tu, H. Y. & Wan, Y. Characteristics of HCN channels and their participation in neuropathic pain. Neurochem. Res. 33, 1979–1989 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Poolos, N. P. The yin and yang of the H-channel and its role in epilepsy. Epilepsy Curr. 4, 3–6 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Schulze-Bahr, E. et al. Pacemaker channel dysfunction in a patient with sinus node disease. J. Clin. Invest. 111, 1537–1545 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ueda, K. et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J. Biol. Chem. 279, 27194–27198 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T. & DiFrancesco, D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N. Engl. J. Med. 354, 151–157 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Nof, E. et al. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 116, 463–470 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Schweizer, P. A. et al. cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control. Circ. Arrhythm. Electrophysiol. 3, 542–552 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Laish-Farkash, A. et al. A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in moroccan jews. J. Cardiovasc. Electrophysiol. 21, 1365–1372 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Harzheim, D. et al. Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP. EMBO J. 27, 692–703 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Herrmann, S., Stieber, J., Stockl, G., Hofmann, F. & Ludwig, A. HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice. EMBO J. 26, 4423–4432 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hoesl, E. et al. Tamoxifen-inducible gene deletion in the cardiac conduction system. J. Mol. Cell. Cardiol. 45, 62–69 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Cerbai, E. & Mugelli, A. If in non-pacemaker cells: role and pharmacological implications. Pharmacol. Res. 53, 416–423 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Mangoni, M. E. & Nargeot, J. Genesis and regulation of the heart automaticity. Physiol. Rev. 88, 919–982 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Stillitano, F. et al. Molecular basis of funny current (If) in normal and failing human heart. J. Mol. Cell. Cardiol. 45, 289–299 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Campbell, J. N. & Meyer, R. A. Mechanisms of neuropathic pain. Neuron 52, 77–92 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bender, R. A. & Baram, T. Z. Hyperpolarization activated cyclic-nucleotide gated (HCN) channels in developing neuronal networks. Prog. Neurobiol. 86, 129–140 (2008). This report shows that developmental HCN channel dysregulation has a role in the generation of epilepsies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chaplan, S. R. et al. Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J. Neurosci. 23, 1169–1178 (2003). This study links upregulation of HCN channels with peripheral neuropathies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kitagawa, J. et al. Mechanisms involved in modulation of trigeminal primary afferent activity in rats with peripheral mononeuropathy. Eur. J. Neurosci. 24, 1976–1986 (2006).

    Article  PubMed  Google Scholar 

  89. Doan, T. N. et al. Differential distribution and function of hyperpolarization-activated channels in sensory neurons and mechanosensitive fibers. J. Neurosci. 24, 3335–3343 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dyhrfjeld-Johnsen, J., Morgan, R. J. & Soltesz, I. Double trouble? Potential for hyperexcitability following both channelopathic up- and downregulation of Ih in epilepsy. Front. Neurosci. 3, 25–33 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Benetos, A., Rudnichi, A., Thomas, F., Safar, M. & Guize, L. Influence of heart rate on mortality in a French population: role of age, gender, and blood pressure. Hypertension 33, 44–52 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Yusuf, S. & Camm, A. J. Sinus tachyarrhythmias and the specific bradycardic agents: a marriage made in heaven? J. Cardiovasc. Pharmacol. Ther. 8, 89–105 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Borer, J. S. Drug insight: If inhibitors as specific heart-rate-reducing agents. Nature Clin. Pract. Cardiovasc. Med. 1, 103–109 (2004).

    Article  CAS  Google Scholar 

  94. Levine, H. J. Rest heart rate and life expectancy. J. Am. Coll. Cardiol. 30, 1104–1106 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Doesch, A. O. et al. Heart rate reduction after heart transplantation with β-blocker versus the selective If channel antagonist ivabradine. Transplantation 84, 988–996 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Bois, P., Guinamard, R., Chemaly, A. E., Faivre, J. F. & Bescond, J. Molecular regulation and pharmacology of pacemaker channels. Curr. Pharm. Des. 13, 2338–2349 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Bucchi, A., Baruscotti, M. & DiFrancesco, D. Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J. Gen. Physiol. 120, 1–13 (2002). This study examines the molecular mechanism of action of ivabradine.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bucchi, A., Tognati, A., Milanesi, R., Baruscotti, M. & DiFrancesco, D. Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels. J. Physiol. 572, 335–346 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Riccioni, G., Vitulano, N. & D'Orazio, N. Ivabradine: beyond heart rate control. Adv. Ther. 26, 12–24 (2009).

    Article  PubMed  Google Scholar 

  100. Cerbai, E. et al. Characterization of the hyperpolarization-activated current, If, in ventricular myocytes from human failing heart. Circulation 95, 568–571 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Hoppe, U. C. et al. Effect of cardiac resynchronization on the incidence of atrial fibrillation in patients with severe heart failure. Circulation 114, 18–25 (2006).

    Article  PubMed  Google Scholar 

  102. Manz, M., Reuter, M., Lauck, G., Omran, H. & Jung, W. A single intravenous dose of ivabradine, a novel If inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology 100, 149–155 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Fox, K., Ford, I., Steg, P. G., Tendera, M. & Ferrari, R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 372, 807–816 (2008). This study reported the results of a large clinical trial (BEAUTIFUL) of ivabradine.

    Article  CAS  PubMed  Google Scholar 

  104. Fox, K. et al. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 372, 817–821 (2008).

    Article  PubMed  Google Scholar 

  105. Swedberg, K. et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376, 875–885 (2010). This study reported the results of a clinical trial (SHIFT) of ivabradine.

    Article  CAS  PubMed  Google Scholar 

  106. Melchiorre, M. et al. Design, synthesis, and preliminary biological evaluation of new isoform-selective f-current blockers. J. Med. Chem. 53, 6773–6777 (2010). This was the first report on the attempts to design subtype-specific HCN channel blockers.

    Article  CAS  PubMed  Google Scholar 

  107. Bois, P., Bescond, J., Renaudon, B. & Lenfant, J. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br. J. Pharmacol. 118, 1051–1057 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. DiFrancesco, D. & Camm, J. A. Heart rate lowering by specific and selective If current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs 64, 1757–1765 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Stieber, J. Ivabradine: pharmacodynamic aspects of its clinical use. Methods Find. Exp. Clin. Pharmacol. 30, 633–641 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Barrow, A. J. & Wu, S. M. Low-conductance HCN1 ion channels augment the frequency response of rod and cone photoreceptors. J. Neurosci. 29, 5841–5853 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Cervetto, L., Demontis, G. C. & Gargini, C. Cellular mechanisms underlying the pharmacological induction of phosphenes. Br. J. Pharmacol. 150, 383–390 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Romanelli, M. N. et al. Isoform-selective HCN blockers. WO Patent 2011/000915 (2011).

  113. Savelieva, I. & Camm, A. J. If inhibition with ivabradine: electrophysiological effects and safety. Drug Saf. 31, 95–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  114. Knaus, A. et al. Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine. Circulation 115, 872–880 (2007). This is a report on the effects of clonidine on HCN channels.

    Article  CAS  PubMed  Google Scholar 

  115. Huang, Z., Walker, M. C. & Shah, M. M. Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis. J. Neurosci. 29, 10979–10988 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Santoro, B. et al. Increased seizure severity and seizure-related death in mice lacking HCN1 channels. Epilepsia 51, 1624–1627 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Shah, M. M., Anderson, A. E., Leung, V., Lin, X. & Johnston, D. Seizure-induced plasticity of h channels in entorhinal cortical layer III pyramidal neurons. Neuron 44, 495–508 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Shin, M., Brager, D., Jaramillo, T. C., Johnston, D. & Chetkovich, D. M. Mislocalization of h channel subunits underlies h channelopathy in temporal lobe epilepsy. Neurobiol. Dis. 32, 26–36 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Dibbens, L. M. et al. Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann. Neurol. 67, 542–546 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Richichi, C. et al. Mechanisms of seizure-induced 'transcriptional channelopathy' of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Neurobiol. Dis. 29, 297–305 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Kitayama, M. et al. Ih blockers have a potential of antiepileptic effects. Epilepsia 44, 20–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Poolos, N. P., Migliore, M. & Johnston, D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nature Neurosci. 5, 767–774 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Surges, R., Freiman, T. M. & Feuerstein, T. J. Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells. Epilepsia 44, 150–156 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Luo, L. et al. Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat. Neuroscience 144, 1477–1485 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Descoeur, J. et al. Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol. Med. 3, 266–278 (2011). This study demonstrates that HCN channels are potential targets for the treatment of oxaliplatin-induced cold hypersensitivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Momin, A., Cadiou, H., Mason, A. & McNaughton, P. A. Role of the hyperpolarization-activated current Ih in somatosensory neurons. J. Physiol. 586, 5911–5929 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Emery, E. C., Young, G. T., Berrocoso, E. M., Chen, L. & McNaughton, P. A. HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333, 1462–1466 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Lee, D. H., Chang, L., Sorkin, L. S. & Chaplan, S. R. Hyperpolarization-activated, cation-nonselective, cyclic nucleotide-modulated channel blockade alleviates mechanical allodynia and suppresses ectopic discharge in spinal nerve ligated rats. J. Pain 6, 417–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Sun, Q., Xing, G. G., Tu, H. Y., Han, J. S. & Wan, Y. Inhibition of hyperpolarization-activated current by ZD7288 suppresses ectopic discharges of injured dorsal root ganglion neurons in a rat model of neuropathic pain. Brain Res. 1032, 63–69 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Yagi, J. & Sumino, R. Inhibition of a hyperpolarization-activated current by clonidine in rat dorsal root ganglion neurons. J. Neurophysiol. 80, 1094–1104 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. Rudolph, U. & Antkowiak, B. Molecular and neuronal substrates for general anaesthetics. Nature Rev. Neurosci. 5, 709–720 (2004).

    Article  CAS  Google Scholar 

  132. Linden, A. M. et al. TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics. J. Pharmacol. Exp. Ther. 323, 924–934 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Sirois, J. E., Pancrazio, J. J., Iii, C. L. & Bayliss, D. A. Multiple ionic mechanisms mediate inhibition of rat motoneurones by inhalation anaesthetics. J. Physiol. 512 (Pt 3), 851–862 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sirois, J. E., Lynch, C. & Bayliss, D. A. Convergent and reciprocal modulation of a leak K+ current and Ih by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones. J. Physiol. 541, 717–729 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Budde, T. et al. Reciprocal modulation of Ih and ITASK in thalamocortical relay neurons by halothane. Pflugers Arch. 456, 1061–1073 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Chen, X. et al. HCN subunit-specific and cAMP-modulated effects of anesthetics on neuronal pacemaker currents. J. Neurosci. 25, 5803–5814 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chen, X., Shu, S., Kennedy, D. P., Willcox, S. C. & Bayliss, D. A. Subunit-specific effects of isoflurane on neuronal Ih in HCN1 knockout mice. J. Neurophysiol. 101, 129–140 (2009). This study shows that general anaesthetics target HCN channels.

    Article  CAS  PubMed  Google Scholar 

  138. Cacheaux, L. P. et al. Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol. J. Pharmacol. Exp. Ther. 315, 517–525 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Meng, Q. T., Xia, Z. Y., Liu, J., Bayliss, D. A. & Chen, X. Local anesthetic inhibits hyperpolarization-activated cationic currents. Mol. Pharmacol. 79, 866–873 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Griguoli, M. et al. Nicotine blocks the hyperpolarization-activated current Ih and severely impairs the oscillatory behavior of oriens-lacunosum moleculare interneurons. J. Neurosci. 30, 10773–10783 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Knop, G. C. et al. Light responses in the mouse retina are prolonged upon targeted deletion of the HCN1 channel gene. Eur. J. Neurosci. 28, 2221–2230 (2008).

    Article  PubMed  Google Scholar 

  142. Moroni, A. et al. Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current If . J. Biol. Chem. 276, 29233–29241 (2001).

    Article  CAS  PubMed  Google Scholar 

  143. Marionneau, C. et al. Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart. J. Physiol. 562, 223–234 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Hurtado, R., Bub, G. & Herzlinger, D. The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis. Kidney Int. 77, 500–508 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Dobrzynski, H. et al. Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart. Circ. Res. 93, 1102–1110 (2003).

    Article  CAS  PubMed  Google Scholar 

  146. McClure, K. J. et al. Discovery of a novel series of selective HCN1 blockers. Bioorg. Med. Chem. Lett. 21, 5197–5201 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the German Research Foundation (the Deutsche Forschungsgemeinschaft).

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Glossary

Pacemaker cells

Cardiac cells that display automaticity. The primary pacemaker cells of the heart are localized in the sinoatrial node region.

Sinoatrial node

Tissue located in the right atrium of the heart that generates cardiac sinus rhythm.

Diastolic depolarization

Slow membrane depolarization that occurs between action potentials (that is, in the diastole of the heart) in pacemaker cells of the cardiac system.

Sinus bradycardia

Heart rhythm that originates from the sinus node with a resting heart rate of 60 beats per minute or less.

Syncope

Partial or complete loss of consciousness, with interruption of awareness of oneself and one's surroundings. Syncope often occurs as a result of an irregular heartbeat.

Chronotropic incompetence

The inability to increase heart rate commensurately with increased activity or demand.

QT prolongation

The QT interval represents the time for electrical activation and inactivation of the ventricles — the lower chambers of the heart. Prolongation of the QT interval can result in the potentially lethal arrythmia known as torsades de pointes.

Torsades de pointes

A form of polymorphous ventricular tachycardia that is associated with prolongation of the cardiac QT interval that can lead to sudden cardiac death.

Inotropic effects

Effects pertaining to the force of muscular contractions, particularly those of the heart.

Absence epilepsy

A form of childhood epilepsy that typically results from abnormal transformation of thalamocortical oscillations.

Temporal lobe epilepsy

A form of epilepsy in which seizures typically involve the hippocampus and adjacent cortices. This form of epilepsy is not thought to have a strong genetic component.

Febrile seizure syndromes

Seizures that take place in children at the onset of or during fever. They are the most common types of seizures in humans, and usually short and benign. However, when they are long (especially longer than 30 minutes), these seizures are associated with a high probability of the development of hippocampal epilepsy (temporal lobe epilepsy) later in life. There are both genetic and environmental contributions to febrile seizures.

Background potassium channels

Potassium channels that are constitutively open or possess high basal activity (sometimes also called 'leaky channels').

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Postea, O., Biel, M. Exploring HCN channels as novel drug targets. Nat Rev Drug Discov 10, 903–914 (2011). https://doi.org/10.1038/nrd3576

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