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Gene Review

HCN1  -  hyperpolarization activated cyclic...

Homo sapiens

Synonyms: BCNG-1, BCNG1, Brain cyclic nucleotide-gated channel 1, EIEE24, HAC-2, ...
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Disease relevance of HCN1

  • After experimental febrile seizures (i.e., early in the epileptogenic process), the preserved and augmented inhibition onto principal cells may lead to reduced HCN1 expression [1].
  • Thus, loss of function of dendritic HCN1 channels in layer 5 pyramidal neurons provides a somato-dendritic mechanism for increasing the synchronization of cortical output, and is therefore likely to play an important role in the generation of absence seizures [2].
  • Continuous cerebral cortical cell lines have been developed from two patients, an 11-month-old with unilateral megalencephaly and a seven-year-old with Rasmussen's encephalitis, designated HCN-1 and HCN-2, respectively [3].
  • We established a cisplatin-resistant human ovarian cancer cell line (HAC2/0.1) from the parent cell line (HAC2/P) by continuous exposure of HAC2/P to 0.1 microgram of cisplatin/ml [4].
  • METHODS: We used human ovarian adenocarcinoma cell lines KF, KFTx (PTX-resistant KF), SK-OV-3, and HAC-2 [5].

High impact information on HCN1

  • Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli [6].
  • Southern blot analysis shows that several other BCNG-related sequences are present in the mouse genome, indicating the emergence of an entire subfamily of ion channel coding genes [7].
  • The 50% inhibitory concentration of CPT-11 for HAC2/0.1 was not reduced by BSO treatment to the level for HAC2/P, even though the GSH content had been reduced more than in HAC2/P [4].
  • 1. The glutathione (GSH) content was higher in HAC2/0.1 than in HAC2/P [4].
  • HAC2/0.1 was 12.1 and 2.0 times as resistant to (4s)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)-carbony loxy]dione hydrochloride trithydrate (CPT-11) and 7-ethyl-10-hydroxy-CPT (SN-38; an active metabolite of CPT-11), respectively, than HAC2/P [4].

Chemical compound and disease context of HCN1


Biological context of HCN1

  • Using computational modeling, we demonstrate that the intrinsically sluggish HCN1 activation kinetics underlie their IV-hysteretic behavior and do not hinder the ability to modulate cardiac pacing [9].
  • Consistent with this notion, when a train of SA nodal-like action potentials was applied in voltage-clamp experiments, HCN1 exhibited pronounced current-voltage (IV)-hysteresis [9].
  • The results show that low millimolar concentrations of Ba2+ reduce the maximal I(h) conductance (IC50 approximately 3-5 mM) in both CA1 pyramidal neurons and in HEK 293 cells without specificity for HCN1 or HCN2 subunits [10].
  • An interactive tool for extracting exons and SNP from genomic sequence: isolation of HCN1 and HCN3 ion channel genes [11].
  • This phenotype shows marked similarity to the current arising from coexpressed HCN1 and HCN2 subunits in oocytes and the native pacemaker current in CA1 pyramidal neurons [12].

Anatomical context of HCN1

  • METHODS AND RESULTS: HCN1, 2 and 4 channels were heterologously expressed in Xenopus laevis oocytes or mammalian Cos7 cells and subjected to voltage clamp [9].
  • In contrast, HCN1 mRNA expression over the GC layer and in individual GCs from epileptic hippocampus was markedly increased once GC neuronal density was reduced by >50% [1].
  • In autopsy and most NHS hippocampi, HCN1 mRNA expression was substantial in pyramidal cell layers and lower in dentate gyrus granule cells (GCs) [1].
  • The presence of HCN1 in the SAN myocytes but not in nearby heart regions, and the electrophysiological properties of the channels formed by it, suggest that HCN1 plays a central and specific role in the formation of SAN pacemaker currents [13].
  • HCN1 shows a high level of expression in apical dendrites of cortical pyramidal neurons and in presynaptic terminals of cerebellar basket cells, structures with a high density of I(h) [14].

Associations of HCN1 with chemical compounds

  • HCN1 channels also showed a marked propofol-induced hyperpolarizing shift in the voltage dependence of activation (EC(50) of 6.7 +/- 1.0 microM) and accelerated deactivation (EC(50) of 4.5 +/- 0.9 microM) [15].
  • Furthermore, similar robust and isoform-selective augmentation of HCN1 mRNA expression was evident also in the pilocarpine animal model of TLE [1].
  • Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels [16].
  • Characterization of the human HCN1 channel and its inhibition by capsazepine [17].
  • Hyperpolarization-activated, cyclic AMP-gated, HCN1-like cation channel: the primary, full-length HCN isoform expressed in a saccular hair-cell layer [18].

Regulatory relationships of HCN1

  • HCN1 mRNA changes were accompanied by enhanced immunoreactivity in the GC dendritic fields and more modest changes in HCN2 mRNA expression [1].

Other interactions of HCN1

  • We also identified HCN1/HCN2 heteromers in mouse brain indicating that heteromeric channels exist in vivo [19].
  • The properties of three HCN channel isoforms (HCN1, HCN2, and HCN4) have been extensively investigated [20].
  • This study further characterizes the distribution pattern of MEF-2A in the mammalian nervous system, demonstrates that MEF-2A colocalizes with DCX in selected neurons, and finds MEF-2A and HCN1 proteins in the neurovasculature network [21].
  • The study described in this paper demonstrates the use of GenoA to study human brain hyperpolarization-activated cation channel genes HCN1 and HCN3 [11].
  • In situ hybridization and immunohistochemistry show that TRIP8b and HCN1 are colocalized, particularly within dendritic arbors of hippocampal CA1 and neocortical layer V pyramidal neurons [14].

Analytical, diagnostic and therapeutic context of HCN1


  1. Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus. Bender, R.A., Soleymani, S.V., Brewster, A.L., Nguyen, S.T., Beck, H., Mathern, G.W., Baram, T.Z. J. Neurosci. (2003) [Pubmed]
  2. Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model. Kole, M.H., Bräuer, A.U., Stuart, G.J. J. Physiol. (Lond.) (2007) [Pubmed]
  3. Human cerebral cortical cell lines from patients with unilateral megalencephaly and Rasmussen's encephalitis. Ronnett, G.V., Hester, L.D., Nye, J.S., Snyder, S.H. Neuroscience (1994) [Pubmed]
  4. Mechanism of cross-resistance to a camptothecin analogue (CPT-11) in a human ovarian cancer cell line selected by cisplatin. Niimi, S., Nakagawa, K., Sugimoto, Y., Nishio, K., Fujiwara, Y., Yokoyama, S., Terashima, Y., Saijo, N. Cancer Res. (1992) [Pubmed]
  5. Activity of docetaxel in paclitaxel-resistant ovarian cancer cells. Sato, S., Kigawa, J., Kanamori, Y., Itamochi, H., Oishi, T., Shimada, M., Iba, T., Naniwa, J., Uegaki, K., Terakawa, N. Cancer Chemother. Pharmacol. (2004) [Pubmed]
  6. 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]
  7. 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. Santoro, B., Grant, S.G., Bartsch, D., Kandel, E.R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  8. Dipyridamole enhances an anti-proliferative effect of interferon in various types of human tumor cells. Suzuki, N., Oiwa, Y., Sugano, I., Inaba, N., Sekiya, S., Fukazawa, I., Yoshida, J., Takakubo, Y., Isogai, E., Saito-Ebihara, M. Int. J. Cancer (1992) [Pubmed]
  9. Non-equilibrium behavior of HCN channels: insights into the role of HCN channels in native and engineered pacemakers. Azene, E.M., Xue, T., Marbán, E., Tomaselli, G.F., Li, R.A. Cardiovasc. Res. (2005) [Pubmed]
  10. Low affinity block of native and cloned hyperpolarization-activated Ih channels by Ba2+ ions. van Welie, I., Wadman, W.J., van Hooft, J.A. Eur. J. Pharmacol. (2005) [Pubmed]
  11. An interactive tool for extracting exons and SNP from genomic sequence: isolation of HCN1 and HCN3 ion channel genes. Liu, Y., Wang, Y., Folander, K., Xie, G., Blevins, R. Journal of bioinformatics and computational biology. (2003) [Pubmed]
  12. Functional heteromerization of HCN1 and HCN2 pacemaker channels. Ulens, C., Tytgat, J. J. Biol. Chem. (2001) [Pubmed]
  13. Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current I(f). Moroni, A., Gorza, L., Beltrame, M., Gravante, B., Vaccari, T., Bianchi, M.E., Altomare, C., Longhi, R., Heurteaux, C., Vitadello, M., Malgaroli, A., DiFrancesco, D. J. Biol. Chem. (2001) [Pubmed]
  14. Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction. Santoro, B., Wainger, B.J., Siegelbaum, S.A. J. Neurosci. (2004) [Pubmed]
  15. Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol. Cacheaux, L.P., Topf, N., Tibbs, G.R., Schaefer, U.R., Levi, R., Harrison, N.L., Abbott, G.W., Goldstein, P.A. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  16. 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]
  17. Characterization of the human HCN1 channel and its inhibition by capsazepine. Gill, C.H., Randall, A., Bates, S.A., Hill, K., Owen, D., Larkman, P.M., Cairns, W., Yusaf, S.P., Murdock, P.R., Strijbos, P.J., Powell, A.J., Benham, C.D., Davies, C.H. Br. J. Pharmacol. (2004) [Pubmed]
  18. Hyperpolarization-activated, cyclic AMP-gated, HCN1-like cation channel: the primary, full-length HCN isoform expressed in a saccular hair-cell layer. Cho, W.J., Drescher, M.J., Hatfield, J.S., Bessert, D.A., Skoff, R.P., Drescher, D.G. Neuroscience (2003) [Pubmed]
  19. Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels. Much, B., Wahl-Schott, C., Zong, X., Schneider, A., Baumann, L., Moosmang, S., Ludwig, A., Biel, M. J. Biol. Chem. (2003) [Pubmed]
  20. 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]
  21. Distribution of constitutively expressed MEF-2A in adult rat and human nervous systems. Ruffle, R.A., Mapley, A.C., Malik, M.K., Labruzzo, S.V., Chabla, J.M., Jose, R., Hallas, B.H., Yu, H.G., Horowitz, J.M., Torres, G. Synapse (2006) [Pubmed]
  22. Different roles for the cyclic nucleotide binding domain and amino terminus in assembly and expression of hyperpolarization-activated, cyclic nucleotide-gated channels. Proenza, C., Tran, N., Angoli, D., Zahynacz, K., Balcar, P., Accili, E.A. J. Biol. Chem. (2002) [Pubmed]
  23. Environmental manipulations early in development alter seizure activity, Ih and HCN1 protein expression later in life. Schridde, U., Strauss, U., Bräuer, A.U., van Luijtelaar, G. Eur. J. Neurosci. (2006) [Pubmed]
  24. Establishment of a CPT-11-resistant human ovarian cancer cell line. Kijima, T., Kubota, N., Nishio, K. Anticancer Res. (1994) [Pubmed]
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