Hcn2

Summary

Gene Symbol: Hcn2
Description: hyperpolarization-activated, cyclic nucleotide-gated K+ 2
Alias: BCNG2, HAC1, trls, potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2, BCNG-2, HAC-1, brain cyclic nucleotide-gated channel 2, hyperpolarization-activated cation channel 1
Species: mouse
Products:     Hcn2

Top Publications

  1. Pian P, Bucchi A, Robinson R, Siegelbaum S. Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2. J Gen Physiol. 2006;128:593-604 pubmed
    ..bath application of exogenous PI(4,5)P(2) reverses the effect of rundown, producing a large depolarizing shift in HCN2 activation...
  2. Zong X, Eckert C, Yuan H, Wahl Schott C, Abicht H, Fang L, et al. A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase. J Biol Chem. 2005;280:34224-32 pubmed
    ..Immunoprecipitation demonstrated that Src binds to and phosphorylates native and heterologously expressed HCN2. Src interacts via its SH3 domain with a sequence of HCN2 encompassing part of the C-linker and the cyclic ..
  3. Chung W, Shin M, JARAMILLO T, Leibel R, LeDuc C, Fischer S, et al. Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2. Neurobiol Dis. 2009;33:499-508 pubmed publisher
    ..mouse, apathetic (ap/ap), and identified the ap mutation as a 4 base pair insertion within the coding region of Hcn2, the gene encoding the h channel subunit 2 (HCN2)...
  4. Much B, Wahl Schott C, Zong X, Schneider A, Baumann L, Moosmang S, et al. Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels. J Biol Chem. 2003;278:43781-6 pubmed
    ..We also identified HCN1/HCN2 heteromers in mouse brain indicating that heteromeric channels exist in vivo...
  5. Abbas S, Ying S, Goldstein P. 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. Neuroscience. 2006;141:1811-25 pubmed
    ..HCN1-4) have been identified, and mRNAs and proteins for HCN channels have been detected in the RTN and VB, with HCN2 and HCN4 being the predominant isoforms...
  6. Santoro B, Liu D, Yao H, Bartsch D, Kandel E, Siegelbaum S, et al. Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell. 1998;93:717-29 pubmed
  7. Yu H, Wu J, Potapova I, Wymore R, Holmes B, Zuckerman J, et al. MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation. Circ Res. 2001;88:E84-7 pubmed
    ..The full text of this article is available at http://www.circresaha.org...
  8. Ludwig A, Zong X, Jeglitsch M, Hofmann F, Biel M. A family of hyperpolarization-activated mammalian cation channels. Nature. 1998;393:587-91 pubmed
    ..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...
  9. Zagotta W, Olivier N, Black K, Young E, Olson R, Gouaux E. Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature. 2003;425:200-5 pubmed
    ..Here we have investigated the mechanism underlying this modulation by studying a carboxy-terminal fragment of HCN2 containing the cyclic nucleotide-binding domain (CNBD) and the C-linker region that connects the CNBD to the pore...
  10. Day M, Carr D, Ulrich S, Ilijic E, Tkatch T, Surmeier D. Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci. 2005;25:8776-87 pubmed
    ..experiments revealed the presence of rapidly activating and deactivating cationic currents attributable to HCN1/HCN2 channels...

Detail Information

Publications73

  1. Pian P, Bucchi A, Robinson R, Siegelbaum S. Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2. J Gen Physiol. 2006;128:593-604 pubmed
    ..bath application of exogenous PI(4,5)P(2) reverses the effect of rundown, producing a large depolarizing shift in HCN2 activation...
  2. Zong X, Eckert C, Yuan H, Wahl Schott C, Abicht H, Fang L, et al. A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase. J Biol Chem. 2005;280:34224-32 pubmed
    ..Immunoprecipitation demonstrated that Src binds to and phosphorylates native and heterologously expressed HCN2. Src interacts via its SH3 domain with a sequence of HCN2 encompassing part of the C-linker and the cyclic ..
  3. Chung W, Shin M, JARAMILLO T, Leibel R, LeDuc C, Fischer S, et al. Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2. Neurobiol Dis. 2009;33:499-508 pubmed publisher
    ..mouse, apathetic (ap/ap), and identified the ap mutation as a 4 base pair insertion within the coding region of Hcn2, the gene encoding the h channel subunit 2 (HCN2)...
  4. Much B, Wahl Schott C, Zong X, Schneider A, Baumann L, Moosmang S, et al. Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels. J Biol Chem. 2003;278:43781-6 pubmed
    ..We also identified HCN1/HCN2 heteromers in mouse brain indicating that heteromeric channels exist in vivo...
  5. Abbas S, Ying S, Goldstein P. 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. Neuroscience. 2006;141:1811-25 pubmed
    ..HCN1-4) have been identified, and mRNAs and proteins for HCN channels have been detected in the RTN and VB, with HCN2 and HCN4 being the predominant isoforms...
  6. Santoro B, Liu D, Yao H, Bartsch D, Kandel E, Siegelbaum S, et al. Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell. 1998;93:717-29 pubmed
  7. Yu H, Wu J, Potapova I, Wymore R, Holmes B, Zuckerman J, et al. MinK-related peptide 1: A beta subunit for the HCN ion channel subunit family enhances expression and speeds activation. Circ Res. 2001;88:E84-7 pubmed
    ..The full text of this article is available at http://www.circresaha.org...
  8. Ludwig A, Zong X, Jeglitsch M, Hofmann F, Biel M. A family of hyperpolarization-activated mammalian cation channels. Nature. 1998;393:587-91 pubmed
    ..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...
  9. Zagotta W, Olivier N, Black K, Young E, Olson R, Gouaux E. Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature. 2003;425:200-5 pubmed
    ..Here we have investigated the mechanism underlying this modulation by studying a carboxy-terminal fragment of HCN2 containing the cyclic nucleotide-binding domain (CNBD) and the C-linker region that connects the CNBD to the pore...
  10. Day M, Carr D, Ulrich S, Ilijic E, Tkatch T, Surmeier D. Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci. 2005;25:8776-87 pubmed
    ..experiments revealed the presence of rapidly activating and deactivating cationic currents attributable to HCN1/HCN2 channels...
  11. Chan C, Shigemoto R, Mercer J, Surmeier D. HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons. J Neurosci. 2004;24:9921-32 pubmed
    ..Single-cell RT-PCR and immunohistochemical approaches revealed robust expression of HCN2 subunits as well as significant levels of HCN1 subunits in GABAergic GP neurons...
  12. Whitaker G, Angoli D, Nazzari H, Shigemoto R, Accili E. HCN2 and HCN4 isoforms self-assemble and co-assemble with equal preference to form functional pacemaker channels. J Biol Chem. 2007;282:22900-9 pubmed
    ..Previous studies have suggested that the HCN2 and HCN4 channel isoforms physically interact when overexpressed in mammalian cells, but whether they are able to ..
  13. Santoro B, Wainger B, Siegelbaum S. Regulation of HCN channel surface expression by a novel C-terminal protein-protein interaction. J Neurosci. 2004;24:10750-62 pubmed
    ..Finally, TRIP8b expression in cultured pyramidal neurons markedly decreases native I(h) density. These data suggest a possible role for TRIP8b in regulating HCN channel density in the plasma membrane. ..
  14. Ludwig A, Budde T, Stieber J, Moosmang S, Wahl C, Holthoff K, et al. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J. 2003;22:216-24 pubmed
    ..Here we show that HCN2-deficient mice exhibit spontaneous absence seizures...
  15. Chen J, Mitcheson J, Lin M, Sanguinetti M. Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel. J Biol Chem. 2000;275:36465-71 pubmed
  16. Decher N, Chen J, Sanguinetti M. Voltage-dependent gating of hyperpolarization-activated, cyclic nucleotide-gated pacemaker channels: molecular coupling between the S4-S5 and C-linkers. J Biol Chem. 2004;279:13859-65 pubmed
    ..We previously reported that the mutation of specific residues in the S4-S5 linker of HCN2 (i.e...
  17. Qu Y, Whitaker G, Hove Madsen L, Tibbits G, Accili E. Hyperpolarization-activated cyclic nucleotide-modulated 'HCN' channels confer regular and faster rhythmicity to beating mouse embryonic stem cells. J Physiol. 2008;586:701-16 pubmed
    ..together, the activation kinetics of I(f) and results from Western blots are consistent with the presence of the HCN2 and HCN3 isoforms...
  18. Santoro B, Grant S, Bartsch D, Kandel E. 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 U S A. 1997;94:14815-20 pubmed
    ..These findings suggest the existence of a new type of ion channel, which is potentially able to modulate membrane excitability in the brain and could respond to regulation by cyclic nucleotides. ..
  19. Zhou L, Siegelbaum S. Gating of HCN channels by cyclic nucleotides: residue contacts that underlie ligand binding, selectivity, and efficacy. Structure. 2007;15:655-70 pubmed
    ..with mutagenesis to identify ligand contacts important for the regulation of the hyperpolarization-activated HCN2 channel by cNMPs...
  20. Macri V, Proenza C, Agranovich E, Angoli D, Accili E. Separable gating mechanisms in a Mammalian pacemaker channel. J Biol Chem. 2002;277:35939-46 pubmed
  21. Deberg H, Brzovic P, Flynn G, Zagotta W, Stoll S. Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides. J Biol Chem. 2016;291:371-81 pubmed publisher
    ..We explain these results with a model where different allosteric mechanisms in the CNBD all converge to have the same effect on the C-linker and render all three cyclic nucleotides similarly potent activators of the channel. ..
  22. Bruzauskaite I, Bironaite D, Bagdonas E, Skeberdis V, Denkovskij J, Tamulevicius T, et al. Relevance of HCN2-expressing human mesenchymal stem cells for the generation of biological pacemakers. Stem Cell Res Ther. 2016;7:67 pubmed publisher
    ..of human mesenchymal stem cells (hMSCs) with the hyperpolarization-activated cyclic nucleotide-gated ion channel 2 (HCN2) gene has been demonstrated to provide biological pacing in dogs with complete heart block...
  23. Ye B, Nerbonne J. Proteolytic processing of HCN2 and co-assembly with HCN4 in the generation of cardiac pacemaker channels. J Biol Chem. 2009;284:25553-9 pubmed publisher
    ..Although previous studies have demonstrated myocardial expression of both the HCN2 and HCN4 subunits, the specific roles of these subunits in the generation of functional myocardial I(f) channels ..
  24. FISHER D, Luu P, Agarwal N, Kurz J, Chetkovich D. Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice. PLoS ONE. 2018;13:e0193012 pubmed publisher
    ..In mice, loss of HCN2 leads to cardiac dysrhythmias, persistent spike-wave discharges similar to those seen in absence epilepsy, ataxia, ..
  25. Chan C, Glajch K, Gertler T, Guzman J, Mercer J, Lewis A, et al. HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease. Nat Neurosci. 2011;14:85-92 pubmed publisher
    ..Viral delivery of HCN2 subunits restored pacemaking and reduced burst spiking in GPe neurons...
  26. Mai W, Janier M, Allioli N, Quignodon L, Chuzel T, Flamant F, et al. Thyroid hormone receptor alpha is a molecular switch of cardiac function between fetal and postnatal life. Proc Natl Acad Sci U S A. 2004;101:10332-7 pubmed
    ..These data describe a physiological situation under which conversion of TRalpha from apo-receptors into holo-receptors, upon changes in T3 availability, plays a determinant role in a developmental process. ..
  27. Hegle A, Nazzari H, Roth A, Angoli D, Accili E. Evolutionary emergence of N-glycosylation as a variable promoter of HCN channel surface expression. Am J Physiol Cell Physiol. 2010;298:C1066-76 pubmed publisher
    ..With the mouse HCN2 isoform as a prototype, HCN channels have further been suggested to require N-glycosylation for function, a ..
  28. Li M, Tonggu L, Tang L, Wang L. Effects of N-glycosylation on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Biochem J. 2015;466:77-84 pubmed publisher
    ..In this study, recombinant wild-type (WT) and glycosylation-defective N380Q HCN2 channels were individually or co-expressed in HEK-293 cells...
  29. Bucchi A, Plotnikov A, Shlapakova I, Danilo P, Kryukova Y, Qu J, et al. Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker. Circulation. 2006;114:992-9 pubmed
    ..We hypothesized that BPM engineered with the use of mE324A mutant murine HCN2 (mHCN2) genes would improve function over mHCN2 and that BPM/EPM tandems confer advantage over either approach ..
  30. Puljung M, Zagotta W. A secondary structural transition in the C-helix promotes gating of cyclic nucleotide-regulated ion channels. J Biol Chem. 2013;288:12944-56 pubmed publisher
    ..We monitored the cAMP-dependent changes in the structure of the C-helix of a C-terminal fragment of HCN2 channels using transition metal ion FRET between fluorophores on the C-helix and metal ions bound between histidine ..
  31. Ying S, Kanda V, Hu Z, Purtell K, King E, Abbott G, et al. Targeted deletion of Kcne2 impairs HCN channel function in mouse thalamocortical circuits. PLoS ONE. 2012;7:e42756 pubmed publisher
    ..Kcne2 deletion was associated with a reduction in whole-brain expression of both HCN1 and HCN2 (but not HCN4), although co-immunoprecipitation from whole-brain lysates failed to detect interaction of KCNE2 with ..
  32. Hofmann F, Fabritz L, Stieber J, Schmitt J, Kirchhof P, Ludwig A, et al. Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart. Cardiovasc Res. 2012;95:317-26 pubmed publisher
    ..Of the four HCN (hyperpolarization-activated cyclic nucleotide-gated channels) isoforms mediating I(f), HCN2 and HCN4 were the predominantly expressed subunits in healthy as well as hypertrophied hearts...
  33. Hattori K, Nakamura K, Hisatomi Y, Matsumoto S, Suzuki M, Harvey R, et al. Arrhythmia induced by spatiotemporal overexpression of calreticulin in the heart. Mol Genet Metab. 2007;91:285-93 pubmed
    ..Our findings support calreticulin being critical for normal heart function and structure. These mice are a useful model for the study of endoplasmic reticulum proteins, such as calreticulin, in various tissues. ..
  34. Kuwahara K, Saito Y, Takano M, Arai Y, Yasuno S, Nakagawa Y, et al. NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J. 2003;22:6310-21 pubmed
    ..Our results indicate NRSF to be a key transcriptional regulator of the fetal cardiac gene program and suggest an important role for NRSF in maintaining normal cardiac structure and function. ..
  35. Chen J, Mitcheson J, Tristani Firouzi M, Lin M, Sanguinetti M. The S4-S5 linker couples voltage sensing and activation of pacemaker channels. Proc Natl Acad Sci U S A. 2001;98:11277-82 pubmed
    ..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...
  36. Bankston J, Camp S, DiMaio F, Lewis A, Chetkovich D, Zagotta W. Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels. Proc Natl Acad Sci U S A. 2012;109:7899-904 pubmed publisher
    ..Here we examine the molecular determinants of TRIP8b binding to HCN2 channels...
  37. 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. 2005;280:13694-700 pubmed
    ..Currents carried by the two cardiac HCN channel isoforms (HCN2 and HCN4) showed the same strong Cl- dependence as the sinoatrial I(f) and decreased to about 10% in the absence of ..
  38. Matt L, Michalakis S, Hofmann F, Hammelmann V, Ludwig A, Biel M, et al. HCN2 channels in local inhibitory interneurons constrain LTP in the hippocampal direct perforant path. Cell Mol Life Sci. 2011;68:125-37 pubmed publisher
    ..To evaluate the role of HCN2 for hippocampal synaptic plasticity, we recorded long-term potentiation (LTP) in the direct perforant path (PP) to ..
  39. El Khoury N, Mathieu S, Marger L, Ross J, El Gebeily G, Ethier N, et al. Upregulation of the hyperpolarization-activated current increases pacemaker activity of the sinoatrial node and heart rate during pregnancy in mice. Circulation. 2013;127:2009-20 pubmed publisher
    ..However, there was a significant increase in HCN2 channel protein expression with no change in HCN4 expression...
  40. Mobley A, Miller A, Araneda R, Maurer L, Muller F, Greer C. Hyperpolarization-activated cyclic nucleotide-gated channels in olfactory sensory neurons regulate axon extension and glomerular formation. J Neurosci. 2010;30:16498-508 pubmed publisher
    ..These data support the hypothesis that the outgrowth and coalescence of OSN axons is, at least in part, subject to activity-dependent mechanisms mediated via HCN channels. ..
  41. Huang J, Huang A, Zhang Q, Lin Y, Yu H. Novel mechanism for suppression of hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by receptor-like tyrosine phosphatase-alpha. J Biol Chem. 2008;283:29912-9 pubmed publisher
    ..found that the receptor-like protein-tyrosine phosphatase-alpha (RPTPalpha) significantly inhibited or eliminated HCN2 channel expression in HEK293 cells...
  42. Ng L, Putrenko I, Baronas V, Van Petegem F, Accili E. Cyclic Purine and Pyrimidine Nucleotides Bind to the HCN2 Ion Channel and Variably Promote C-Terminal Domain Interactions and Opening. Structure. 2016;24:1629-1642 pubmed publisher
    Cyclic AMP is thought to facilitate the opening of the HCN2 channel by binding to a C-terminal domain and promoting or inhibiting interactions between subunits...
  43. Della Santina L, Piano I, Cangiano L, Caputo A, Ludwig A, Cervetto L, et al. Processing of retinal signals in normal and HCN deficient mice. PLoS ONE. 2012;7:e29812 pubmed publisher
    ..mice models and of in vitro (patch-clamp) and in vivo (ERG) recordings of retinal activity we show that HCN1 and HCN2 channels are expressed at distinct retinal sites and serve different functions...
  44. Herrmann S, Layh B, Ludwig A. Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart. J Mol Cell Cardiol. 2011;51:997-1006 pubmed publisher
    ..The specificity of antibodies used was strictly confirmed by the use of HCN1, HCN2 and HCN4 knockout animals...
  45. Sartiani L, Bochet P, Cerbai E, Mugelli A, Fischmeister R. Functional expression of the hyperpolarization-activated, non-selective cation current I(f) in immortalized HL-1 cardiomyocytes. J Physiol. 2002;545:81-92 pubmed
    ..cyclic nucleotide-gated channels (HCN) expressed in HL-1 cells demonstrated major contributions of HCN1 and HCN2 channel isoforms to I(f) current...
  46. Wu S, Vysotskaya Z, Xu X, Xie C, Liu Q, Zhou L. State-dependent cAMP binding to functioning HCN channels studied by patch-clamp fluorometry. Biophys J. 2011;100:1226-32 pubmed publisher
    ..Our results provide what we believe to be new insights into the cAMP-dependent gating in HCN channel and the interpretation of protein allostery for general ligand-gated channels and receptors. ..
  47. Puljung M, Deberg H, Zagotta W, Stoll S. Double electron-electron resonance reveals cAMP-induced conformational change in HCN channels. Proc Natl Acad Sci U S A. 2014;111:9816-21 pubmed publisher
    ..These results provide a basis for understanding how the binding of cAMP is coupled to channel opening in HCN and related channels. ..
  48. Tran N, Proenza C, Macri V, Petigara F, Sloan E, Samler S, et al. A conserved domain in the NH2 terminus important for assembly and functional expression of pacemaker channels. J Biol Chem. 2002;277:43588-92 pubmed
    ..Previously, we suggested that the NH(2) termini of the mouse HCN2 isoform were important for subunit co-assembly and functional channel expression...
  49. 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. 2001;276:6313-9 pubmed
    ..Here we demonstrate that HCN2, a member of the HCN channel family, is directly modulated by the intracellular pH in the physiological range...
  50. Ramakrishnan N, Drescher M, Khan K, Hatfield J, Drescher D. HCN1 and HCN2 proteins are expressed in cochlear hair cells: HCN1 can form a ternary complex with protocadherin 15 CD3 and F-actin-binding filamin A or can interact with HCN2. J Biol Chem. 2012;287:37628-46 pubmed publisher
    ..is mediated by amino-terminal sequence specific to HCN1 and is not replicated by analogous specific peptides for HCN2 or HCN4 nor by amino-terminal sequence conserved across HCN isoforms utilized in channel formation...
  51. Emery E, Young G, Berrocoso E, Chen L, McNaughton P. HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science. 2011;333:1462-6 pubmed publisher
    ..We found that genetic deletion of HCN2 removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing ..
  52. Proenza C, Angoli D, Agranovich E, Macri V, Accili E. Pacemaker channels produce an instantaneous current. J Biol Chem. 2002;277:5101-9 pubmed
    ..Here, we report that the mouse HCN2 pacemaker channel isoform also produced a large instantaneous current (I(inst(HCN2))) in addition to the well ..
  53. Macri V, Nazzari H, McDonald E, Accili E. Alanine scanning of the S6 segment reveals a unique and cAMP-sensitive association between the pore and voltage-dependent opening in HCN channels. J Biol Chem. 2009;284:15659-67 pubmed publisher
    ..Accordingly, we performed a 22-residue alanine/valine scan of the distal pore of the HCN2 isoform and show that the effects of mutations on channel opening and on the steepness of the response of the ..
  54. Wicks N, Wong T, Sun J, Madden Z, Young E. Cytoplasmic cAMP-sensing domain of hyperpolarization-activated cation (HCN) channels uses two structurally distinct mechanisms to regulate voltage gating. Proc Natl Acad Sci U S A. 2011;108:609-14 pubmed publisher
    ..Thus the liganded and the unliganded forms of the CSD respectively provide the structural determinants for open-state trapping and autoinhibition, such that two distinct mechanisms for cAMP regulation can operate in one receptor. ..
  55. Cheng L, Kinard K, Rajamani R, Sanguinetti M. Molecular mapping of the binding site for a blocker of hyperpolarization-activated, cyclic nucleotide-modulated pacemaker channels. J Pharmacol Exp Ther. 2007;322:931-9 pubmed
    ..the HCN channel blocker, ZD7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride] on HCN2 channels that were heterologously expressed in Xenopus oocytes...
  56. Carlson A, Rosenbaum J, Brelidze T, Klevit R, Zagotta W. Flavonoid regulation of HCN2 channels. J Biol Chem. 2013;288:33136-45 pubmed publisher
    ..Here, we report that, like cAMP, the flavonoid fisetin potentiates HCN2 channel gating...
  57. Seo H, Seol M, Lee K. Differential expression of hyperpolarization-activated cyclic nucleotide-gated channel subunits during hippocampal development in the mouse. Mol Brain. 2015;8:13 pubmed publisher
    ..Here we examined the developmental expression of the brain-enriched HCN1, HCN2, and HCN4 isoforms of HCN channels in mouse hippocampus from embryonic to postnatal stages...
  58. Lewis A, Vaidya S, Blaiss C, Liu Z, Stoub T, Brager D, et al. Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J Neurosci. 2011;31:7424-40 pubmed publisher
    ..We observed similar resistance to behavioral despair in distinct mutant mice lacking HCN1 or HCN2. These data demonstrate that interaction with the auxiliary subunit TRIP8b is a major mechanism underlying proper ..
  59. Berrera M, Pantano S, Carloni P. cAMP Modulation of the cytoplasmic domain in the HCN2 channel investigated by molecular simulations. Biophys J. 2006;90:3428-33 pubmed
    ..nucleotide binding domain (CNBD) in the presence and absence of cAMP, based on the available crystal structure of HCN2 from mouse...
  60. Meuth S, Kanyshkova T, Meuth P, Landgraf P, Munsch T, Ludwig A, et al. Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. J Neurophysiol. 2006;96:1517-29 pubmed
    ..Quantitative determination of mRNA expression levels and immunocytochemical staining demonstrated that TASK3 and HCN2 channels represent the dominant thalamic isoforms and are coexpressed in TC neurons...
  61. Zhao X, Bucchi A, Oren R, Kryukova Y, Dun W, Clancy C, et al. In vitro characterization of HCN channel kinetics and frequency dependence in myocytes predicts biological pacemaker functionality. J Physiol. 2009;587:1513-25 pubmed publisher
    ..Previous experiments creating HCN-based biological pacemakers in vivo found that an engineered HCN2/HCN1 chimeric channel (HCN212) resulted in significantly faster rates than HCN2, interrupted by 1-5 s pauses...
  62. Chen S, Wang J, Zhou L, George M, Siegelbaum S. Voltage sensor movement and cAMP binding allosterically regulate an inherently voltage-independent closed-open transition in HCN channels. J Gen Physiol. 2007;129:175-88 pubmed
    ..Here we have addressed the mechanism of this dual regulation for HCN2 channels, which activate with slow kinetics that are strongly accelerated by cAMP, and HCN1 channels, which ..
  63. Honsa P, Pivonkova H, Harantova L, Butenko O, Kriška J, Dzamba D, et al. Increased expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in reactive astrocytes following ischemia. Glia. 2014;62:2004-21 pubmed publisher
    ..Collectively, our results demonstrate that regardless of the type of ischemic injury, reactive astrocytes express HCN channels, which could therefore be an important therapeutic target in poststroke therapy. ..
  64. Deberg H, Bankston J, Rosenbaum J, Brzovic P, Zagotta W, Stoll S. Structural mechanism for the regulation of HCN ion channels by the accessory protein TRIP8b. Structure. 2015;23:734-44 pubmed publisher
    ..resonance (EPR) to show that TRIP8b binds to the apo state of the cyclic nucleotide binding domain (CNBD) of HCN2 channels without changing the overall domain structure...
  65. Shin M, Simkin D, Suyeoka G, Chetkovich D. Evaluation of HCN2 abnormalities as a cause of juvenile audiogenic seizures in Black Swiss mice. Brain Res. 2006;1083:14-20 pubmed
    ..This region includes Hcn2, the gene encoding the hyperpolarization-activated cyclic nucleotide-gated channel subunit 2 (HCN2), an ion channel ..
  66. Horwitz G, Risner Janiczek J, Jones S, Holt J. HCN channels expressed in the inner ear are necessary for normal balance function. J Neurosci. 2011;31:16814-25 pubmed publisher
    ..4 nS. I(h) was inhibited by ZD7288, cilobradine, and by adenoviral expression of a dominant-negative form of HCN2. To determine which HCN subunits carried I(h), we examined hair cells from mice deficient in Hcn1, 2, or both...
  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. 2011;6:e17078 pubmed publisher
    ..Here, we show for the first time that in the HCN2 channel cGMP can also exert an inhibitory effect on gating via cGMP-dependent protein kinase II (cGKII)-mediated ..
  68. Brager D, Akhavan A, Johnston D. Impaired dendritic expression and plasticity of h-channels in the fmr1(-/y) mouse model of fragile X syndrome. Cell Rep. 2012;1:225-33 pubmed
    ..Dendritic expression of the h-channel subunit HCN1, but not HCN2, was higher in the CA1 region of fmr1(-/y) mice...
  69. Rozario A, Turbendian H, Fogle K, Olivier N, Tibbs G. Voltage-dependent opening of HCN channels: Facilitation or inhibition by the phytoestrogen, genistein, is determined by the activation status of the cyclic nucleotide gating ring. Biochim Biophys Acta. 2009;1788:1939-49 pubmed publisher
    ..8 mV + or - 0.9 versus +2.2 mV + or - 0.6) and hyperpolarizes gating of HCN2 (-4.8 mV + or - 1.0) but depolarizes gating of HCN2-R591E (+13.2 mV + or - 2.1)...
  70. Fried H, Kaupp U, Muller F. Hyperpolarization-activated and cyclic nucleotide-gated channels are differentially expressed in juxtaglomerular cells in the olfactory bulb of mice. Cell Tissue Res. 2010;339:463-79 pubmed publisher
    ..The staining patterns are consistent with the possibility that both homomeric and heteromeric HCN channels are involved in oscillations of the membrane potential of juxtaglomerular cells. ..
  71. Vemana S, Pandey S, Larsson H. Intracellular Mg2+ is a voltage-dependent pore blocker of HCN channels. Am J Physiol Cell Physiol. 2008;295:C557-65 pubmed publisher
    ..53 mM in HCN2 channels and 0.82 mM in HCN1 channels at +50 mV...
  72. Schweizer P, Yampolsky P, Malik R, Thomas D, Zehelein J, Katus H, et al. Transcription profiling of HCN-channel isotypes throughout mouse cardiac development. Basic Res Cardiol. 2009;104:621-9 pubmed publisher
    ..After birth, however, HCN isotype transcription changed remarkably, showing increased levels of HCN1, HCN2 and HCN4 in the atrium and of HCN2 and HCN4 in the ventricle...
  73. Michels G, Er F, Khan I, Südkamp M, Herzig S, Hoppe U. Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation. 2005;111:399-404 pubmed
    ..Single-channel properties of cells cotransfected with HCN2 and HCN4 were distinct from cells expressing HCN2 or HCN4 alone, demonstrating that different HCN isoforms can ..