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Gene Review

HCN4  -  hyperpolarization activated cyclic...

Homo sapiens

Synonyms: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
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Disease relevance of HCN4

  • Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia [1].
  • These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions [1].
  • In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4 [1].
  • We found that sinus bradycardia in members of a large family was associated with a mutation in the gene coding for the pacemaker HCN4 ion channel [2].
  • CONCLUSIONS: The widespread distribution of HCN4 can explain the widespread location of the leading pacemaker site during sinus rhythm, the extensive region of tissue that has to be ablated to stop sinus rhythm, and the widespread distribution of ectopic foci responsible for atrial tachycardia [3].

High impact information on HCN4

  • Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli [4].
  • We thus conclude that hHCN2 and hHCN4 may underlie the fast and slow component of cardiac If, respectively [5].
  • Measurements of the fractional Ca(2+) current showed that it constitutes 0.60 +/- 0.02% of the net inward current through HCN4 at -120 mV [6].
  • Heterologous expression of hHCN4 produces channels of unusually slow kinetics of activation and inactivation [7].
  • Within the brain, the thalamus is the predominant area of hHCN4 expression [7].

Biological context of HCN4

  • In both cell types, co-expressed KCNE2 enhanced HCN4-generated current amplitudes, slowed the activation kinetics and shifted the voltage for half-maximal activation of currents to more negative voltages [8].
  • The HCN4 channel shows differential expression patterns during the embryonic development and hypertrophy of hearts [9].
  • The hHCN4 gene was mapped to chromosome band 15q24-q25 [7].

Anatomical context of HCN4

  • Finally, HCN4 transcripts were prominently expressed selectively in the thalamus and olfactory bulb [10].
  • To determine whether KCNE2 can also modulate the slow component of native I(f/h/q) currents, we co-expressed KCNE2 with HCN4 in Xenopus oocytes and in Chinese hamster ovary (CHO) cells and analysed the resulting currents using two-electrode voltage-clamp and patch-clamp techniques, respectively [8].
  • Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system [1].
  • To investigate the influence of cellular environment on the gating of HCN channels, we compared the functional characteristics of HCN2 and HCN4, the two major ventricular isoforms, when over-expressed in a normal context (neonatal myocytes) and in a heterologous context (HEK 293 cells) [11].
  • HCN4 was not expressed in the pulmonary veins [3].

Associations of HCN4 with chemical compounds

  • Replacement of leucine 272 in S1 of HCN4 by the corresponding phenylalanine present in HCN2 decreased tau act of HCN4 to 149 ms [12].
  • In this study we have investigated the blocking action of ivabradine on mouse (m) HCN1 and human (h) HCN4 channels heterologously expressed in HEK 293 cells [13].
  • Three hours following an injection of propofol sufficient to produce loss-of-righting reflex in mice (P35), I(h) was decreased, and this was accompanied by a corresponding decrease in HCN2 and HCN4 immunoreactivity in thalamocortical neurons in vivo [14].
  • Lipid raft disruption by cell incubation with methyl-beta-cyclodextrin (MbetaCD) impaired specific HCN4 localization [15].

Regulatory relationships of HCN4

  • Independent of cell type, HCN4 activates substantially slower than HCN2 and with a half-maximum activation voltage approximately equal 10 mV less negative [11].

Other interactions of HCN4

  • Consistent with these electrophysiological results, the carboxy-terminal tail of KCNE2, but not of other KCNE subunits, interacted with the carboxy-terminal tail of HCN4 in yeast two-hybrid assays [8].
  • The properties of three HCN channel isoforms (HCN1, HCN2, and HCN4) have been extensively investigated [16].
  • We verified that members of the HCN channel family (mHCN1, hHCN2, hHCN4) also have properties not complying with HH gating, such as sigmoidal activation and deactivation, activation deviating from fixed power of an exponential, removal of activation "delay" by preconditioning hyperpolarization [17].
  • These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations [1].
  • Reverse transcriptase-polymerase chain reaction analysis revealed the presence of mRNA transcripts for HCN2, HCN3 and HCN4 subunits in these cells [18].

Analytical, diagnostic and therapeutic context of HCN4


  1. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. Ueda, K., Nakamura, K., Hayashi, T., Inagaki, N., Takahashi, M., Arimura, T., Morita, H., Higashiuesato, Y., Hirano, Y., Yasunami, M., Takishita, S., Yamashina, A., Ohe, T., Sunamori, M., Hiraoka, M., Kimura, A. J. Biol. Chem. (2004) [Pubmed]
  2. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. Milanesi, R., Baruscotti, M., Gnecchi-Ruscone, T., DiFrancesco, D. N. Engl. J. Med. (2006) [Pubmed]
  3. Extended atrial conduction system characterised by the expression of the HCN4 channel and connexin45. Yamamoto, M., Dobrzynski, H., Tellez, J., Niwa, R., Billeter, R., Honjo, H., Kodama, I., Boyett, M.R. Cardiovasc. Res. (2006) [Pubmed]
  4. Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Stevens, D.R., Seifert, R., Bufe, B., Müller, F., Kremmer, E., Gauss, R., Meyerhof, W., Kaupp, U.B., Lindemann, B. Nature (2001) [Pubmed]
  5. Two pacemaker channels from human heart with profoundly different activation kinetics. Ludwig, A., Zong, X., Stieber, J., Hullin, R., Hofmann, F., Biel, M. EMBO J. (1999) [Pubmed]
  6. Calcium influx through hyperpolarization-activated cation channels (I(h) channels) contributes to activity-evoked neuronal secretion. Yu, X., Duan, K.L., Shang, C.F., Yu, H.G., Zhou, Z. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  7. Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Seifert, R., Scholten, A., Gauss, R., Mincheva, A., Lichter, P., Kaupp, U.B. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  8. KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents. Decher, N., Bundis, F., Vajna, R., Steinmeyer, K. Pflugers Arch. (2003) [Pubmed]
  9. NRSF regulates the developmental and hypertrophic changes of HCN4 transcription in rat cardiac myocytes. Kuratomi, S., Kuratomi, A., Kuwahara, K., Ishii, T.M., Nakao, K., Saito, Y., Takano, M. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  10. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Moosmang, S., Biel, M., Hofmann, F., Ludwig, A. Biol. Chem. (1999) [Pubmed]
  11. Functional comparison of HCN isoforms expressed in ventricular and HEK 293 cells. Qu, J., Altomare, C., Bucchi, A., DiFrancesco, D., Robinson, R.B. Pflugers Arch. (2002) [Pubmed]
  12. Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4. Stieber, J., Thomer, A., Much, B., Schneider, A., Biel, M., Hofmann, F. J. Biol. Chem. (2003) [Pubmed]
  13. Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels. Bucchi, A., Tognati, A., Milanesi, R., Baruscotti, M., Difrancesco, D. J. Physiol. (Lond.) (2006) [Pubmed]
  14. Propofol block of I(h) contributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons. Ying, S.W., Abbas, S.Y., Harrison, N.L., Goldstein, P.A. Eur. J. Neurosci. (2006) [Pubmed]
  15. Localization of pacemaker channels in lipid rafts regulates channel kinetics. Barbuti, A., Gravante, B., Riolfo, M., Milanesi, R., Terragni, B., DiFrancesco, D. Circ. Res. (2004) [Pubmed]
  16. The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. Mistrík, P., Mader, R., Michalakis, S., Weidinger, M., Pfeifer, A., Biel, M. J. Biol. Chem. (2005) [Pubmed]
  17. Integrated allosteric model of voltage gating of HCN channels. Altomare, C., Bucchi, A., Camatini, E., Baruscotti, M., Viscomi, C., Moroni, A., DiFrancesco, D. J. Gen. Physiol. (2001) [Pubmed]
  18. Dependence of hyperpolarisation-activated cyclic nucleotide-gated channel activity on basal cyclic adenosine monophosphate production in spontaneously firing GH3 cells. Kretschmannova, K., Gonzalez-Iglesias, A.E., Tomić, M., Stojilkovic, S.S. J. Neuroendocrinol. (2006) [Pubmed]
  19. Compartmental distribution of hyperpolarization-activated cyclic-nucleotide-gated channel 2 and hyperpolarization-activated cyclic-nucleotide-gated channel 4 in thalamic reticular and thalamocortical relay neurons. Abbas, S.Y., Ying, S.W., Goldstein, P.A. Neuroscience (2006) [Pubmed]
  20. The hyperpolarization-activated current If in ventricular myocytes of non-transgenic and beta2-adrenoceptor overexpressing mice. Graf, E.M., Heubach, J.F., Ravens, U. Naunyn Schmiedebergs Arch. Pharmacol. (2001) [Pubmed]
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