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Gene Review

HCN2  -  hyperpolarization activated cyclic...

Homo sapiens

Synonyms: BCNG-2, BCNG2, Brain cyclic nucleotide-gated channel 2, HAC-1, Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
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Disease relevance of HCN2

  • This isoform- and region-specific transcriptional regulation of the HCNs required neuronal activity rather than hyperthermia alone, correlated with seizure duration, and favored the formation of slow-kinetics HCN2-encoded channels [1].
  • In conclusion, although left ventricular hypertrophy involves an up-regulation of I (f) and its molecular correlate HCN2 in the rat ventricle, its contribution to diastolic depolarization would be limited by the low values of I (f) density at potentials close to the resting potential of the ventricular cells [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].

High impact information on HCN2

  • The HCN2 gene is localized on human chromosome 19p13.3 and contains eight exons spanning approximately 27 kb [4].
  • We thus conclude that hHCN2 and hHCN4 may underlie the fast and slow component of cardiac If, respectively [4].
  • Here, we used alanine-scanning mutagenesis of the HCN2 S4-S5 linker to identify three residues, E324, Y331, and R339, that when mutated disrupted normal channel closing [5].
  • Surprisingly, HEK-293 cells were found to contain mRNA for HCN2 and HCN3 although we have not detected a significant and consistent endogenous I(f)-like current in these cells [6].
  • Exchange of the ion-conducting pore region was sufficient to switch the Cl- dependence from HCN1- to HCN2-type and vice versa [7].

Biological context of HCN2

  • Tunicamycin, an inhibitor of N-linked glycosylation, blocked surface membrane expression of HCN2 [8].
  • Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4 [9].
  • Injection of 50 nl intracellular solution resulted in a current increase of 20%, indicating that an increase in cell volume also under isoosmotic conditions may lead to activation of HCN2 [10].
  • Indeed, HCN2 channels, which have intermediate activation time constants and delays, displayed and intermediate hysteretic phenotype [11].
  • 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 [12].

Anatomical context of HCN2

  • Similarly, a mutant HCN2 channel in which the putative N-glycosylation site in the loop between S5 and the pore helix was replaced by glutamine (HCN2N380Q) was not inserted into the plasma membrane and did not yield detectable whole-cell currents [8].
  • In contrast, HCN2 transcripts were found at high levels nearly ubiquitously in the brain, and the strongest signals were seen in the olfactory bulb, hippocampus, thalamus and brain stem [13].
  • Consistent with this is the recent description of KCNE2, which is highly expressed in the sinoatrial node, as a beta-subunit of rapidly activating HCN1 and HCN2 channels [14].
  • HCN2 channels were coexpressed with aquaporin1 in Xenopus laevis oocytes and currents were monitored using a two-electrode voltage-clamp [10].
  • The increase in HCN2 current induced by cell swelling could be abolished by cytochalasin D treatment, indicating that an intact F-actin cytoskeleton is a prerequisite for the swelling-induced current [10].

Associations of HCN2 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 [9].
  • Here we studied the effects of propofol on recombinant HCN1, HCN2, and HCN4 channels and found that the drug inhibits and slows activation of all three channels at clinically relevant concentrations [15].
  • A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2 [16].
  • A synthetic short chain analogue of PI(4,5)P(2), dioctanoyl phosphatidylinositol 4,5-bisphosphate, shifts the HCN2 activation curve to more positive potentials in a dose-dependent manner [17].
  • VIC in both spHCN and HCN2 was blocked rapidly both by ZD7288 (an HCN channel blocker that is thought to bind in the conduction pore) and by application of Cd2+ to channels containing an introduced cysteine in the pore (spHCN-464C or HCN2-436C) [18].

Regulatory relationships of HCN2

  • Independent of cell type, HCN4 activates substantially slower than HCN2 and with a half-maximum activation voltage approximately equal 10 mV less negative [19].
  • HCN1 mRNA changes were accompanied by enhanced immunoreactivity in the GC dendritic fields and more modest changes in HCN2 mRNA expression [20].
  • Electrophysiological properties of inward rectifier potassium current (I (K1)) and hyperpolarization-activated inward current (I (f)) and the protein expression of the Kir2.1 subfamily and the hyperpolarization-activated cation channel 2 (HCN2) and HCN4 were studied in control and hypertrophied myocytes [2].

Other interactions of HCN2

  • We also identified HCN1/HCN2 heteromers in mouse brain indicating that heteromeric channels exist in vivo [8].
  • Surprisingly, HCN2 and HCN3 did not coassemble to heteromeric channels [8].
  • 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 [21].
  • HCN1 and HCN2 expression were measured using in situ hybridization and immunocytochemistry in hippocampi from three groups: TLE with hippocampal sclerosis (HS; n = 17), epileptic hippocampi without HS, or non-HS (NHS; n = 10), and autopsy material (n = 10) [20].
  • Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels [22].

Analytical, diagnostic and therapeutic context of HCN2


  1. Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner. Brewster, A., Bender, R.A., Chen, Y., Dube, C., Eghbal-Ahmadi, M., Baram, T.Z. J. Neurosci. (2002) [Pubmed]
  2. I (K1) and I (f) in ventricular myocytes isolated from control and hypertrophied rat hearts. Fernández-Velasco, M., Ruiz-Hurtado, G., Delgado, C. Pflugers Arch. (2006) [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. 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]
  5. The S4-S5 linker couples voltage sensing and activation of pacemaker channels. Chen, J., Mitcheson, J.S., Tristani-Firouzi, M., Lin, M., Sanguinetti, M.C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  6. Endogenous channels in HEK cells and potential roles in HCN ionic current measurements. Varghese, A., Tenbroek, E.M., Coles, J., Sigg, D.C. Prog. Biophys. Mol. Biol. (2006) [Pubmed]
  7. An arginine residue in the pore region is a key determinant of chloride dependence in cardiac pacemaker channels. Wahl-Schott, C., Baumann, L., Zong, X., Biel, M. J. Biol. Chem. (2005) [Pubmed]
  8. 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]
  9. 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]
  10. Hypoosmotic cell swelling as a novel mechanism for modulation of cloned HCN2 channels. Calloe, K., Elmedyb, P., Olesen, S.P., Jorgensen, N.K., Grunnet, M. Biophys. J. (2005) [Pubmed]
  11. 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]
  12. 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]
  13. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Moosmang, S., Biel, M., Hofmann, F., Ludwig, A. Biol. Chem. (1999) [Pubmed]
  14. 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]
  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. A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2. Zong, X., Stieber, J., Ludwig, A., Hofmann, F., Biel, M. J. Biol. Chem. (2001) [Pubmed]
  17. Regulation of Gating and Rundown of HCN Hyperpolarization-activated Channels by Exogenous and Endogenous PIP2. Pian, P., Bucchi, A., Robinson, R.B., Siegelbaum, S.A. J. Gen. Physiol. (2006) [Pubmed]
  18. Distinct populations of HCN pacemaker channels produce voltage-dependent and voltage-independent currents. Proenza, C., Yellen, G. J. Gen. Physiol. (2006) [Pubmed]
  19. 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]
  20. 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]
  21. 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]
  22. Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. Meuth, S.G., Kanyshkova, T., Meuth, P., Landgraf, P., Munsch, T., Ludwig, A., Hofmann, F., Pape, H.C., Budde, T. J. Neurophysiol. (2006) [Pubmed]
  23. 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]
  24. 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]
  25. 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]
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