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HCN4

Family: Cyclic nucleotide-regulated channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Voltage Dependence
Activators
Pore Blockers
Tissue Distribution
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1203 15q24-q25 HCN4 hyperpolarization activated cyclic nucleotide-gated potassium channel 4 7
Mouse 6 1 1201 9 C Hcn4 hyperpolarization-activated, cyclic nucleotide-gated K+ 4 15
Rat 6 1 1198 8q24 Hcn4 hyperpolarization activated cyclic nucleotide-gated potassium channel 4 10
Previous and Unofficial Names
HAC4
BCNG3
hyperpolarization activated cyclic nucleotide-gated potassium channel 4
hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4)
hyperpolarization-activated, cyclic nucleotide-gated K+ 4
hyperpolarization-activated, cyclic nucleotide-gated potassium channel 4 (HCN4)
potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
Database Links
Ensembl ENSG00000138622 (Hs), ENSMUSG00000032338 (Mm), ENSRNOG00000009450 (Rn)
Entrez Gene 10021 (Hs), 330953 (Mm), 59266 (Rn)
GeneCards HCN4 (Hs)
GenitoUrinary Development Molecular Anatomy Project Hcn4 (Mm)
HomoloGene 3997 (Hs)
Human Protein Reference Database 09240 (Hs)
InterPro Q9Y3Q4 (Hs), O70507 (Mm), Q9JKA7 (Rn)
KEGG Gene hsa:10021 (Hs), mmu:330953 (Mm), rno:59266 (Rn)
OMIM 605206 (Hs)
Orphanet Gene ORPHA122381 (Hs)
PharmGKB Gene PA394 (Hs)
PhosphoSitePlus Q9Y3Q4 (Hs), O70507 (Mm), Q9JKA7 (Rn)
Protein Ontology (PRO) PRO:000000708 (Hs)
RefSeq Nucleotide NM_005477 (Hs), NM_001081192 (Mm), NM_021658 (Rn)
RefSeq Protein NP_005468 (Hs), NP_001074661 (Mm), NP_067690 (Rn)
TreeFam ENSG00000138622 (Hs), ENSMUSG00000032338 (Mm), ENSRNOG00000009450 (Rn)
UniGene Hs. 655151 (Hs)
UniProt Q9Y3Q4 (Hs), O70507 (Mm), Q9JKA7 (Rn)
Wikipedia HCN4
Cyclic nucleotide-regulated channels
Search for 3D structures on the PDB
Search by keyword: Cyclic nucleotide-regulated channels HCN4 Search by accession number: O70507, Q9JKA7, Q9Y3Q4
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
KCNE2 3
Other Associated Proteins
Name References
Not determined
Ion Selectivity and Conductance
Species:  Human
Rank order:  K+ > Na+ > Ca2+ [17.4 pS]
References:  7-8,24
Ion Selectivity and Conductance Comments
Fractional Ca2+ current makes up only 0.60% of the net inward current [24].
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -98.0 1000.0 – 387.0 3 Xenopus laevis oocyte Human
Inactivation  - -
Comments  V0.5 and τ-values are strongly influenced by experimental parameters such as temperature, pH and pulse protocol.
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -75.0 – -109.0 (median: -82.0) 2000.0 – 660.0 7,13,17,21 HEK 293 cells. Human
Inactivation  - -
Comments  V0.5 and τ-values are strongly influenced by experimental parameters such as temperature, pH and pulse protocol.
Activators (Human)
cAMP > cGMP
Activator Comments
cAMP and cGMP induce a shift of V0.5 by +10 to +25 mV [7,17,21].
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
cilobradine Hs 6.0 pIC50 - -40.0 22
ivabradine Hs 5.7 pIC50 - -40.0 22
zatebradine Hs 5.7 pIC50 - -40.0 22
clonidine Mm 5.0 pIC50 - -40.0 6
ZD7288 Hs 4.7 pIC50 - -40.0 21
Cs+ Hs 3.8 pIC50 - -40.0 21
View species-specific pore blocker tables
Tissue Distribution
Heart (highest expression in the sino-atrial region), brain, testis.
Species:  Human
Technique:  Northern Blot
References:  7,17
Brain, heart.
Species:  Mouse
Technique:  Northern Blot
References:  15
Brain (high levels in thalamus and olfactory bulb).
Species:  Mouse
Technique:  In situ hybridisation
References:  11
Taste cells.
Species:  Mouse
Technique:  In situ hybridisation
References:  19
Heart.
Species:  Rat
Technique:  RNAse protection assay
References:  18
Retina.
Species:  Rat
Technique:  Immunohistochemistry
References:  12
Physiological Functions
Transduction of sour taste.
Species:  Rat
Tissue:  Vallate papilla
References:  19
Development of cardiac pacemaker cells, heart rate control.
Species:  None
Tissue:  Pacemaker region of heart.
References:  14
Physiological Consequences of Altering Gene Expression
Knockout of the HCN4 gene results in embryonic lethality. Embryos are bradycardic and unable to speed up heart reate.
Species:  Mouse
Tissue:  Heart
Technique:  Knockout
References:  20
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Hcn4tm1.1Jsr Hcn4tm1.1Jsr/Hcn4tm1.1Jsr
involves: 129/Sv * C57BL/6		 MGI:1298209  MP:0001629 abnormal heart rate PMID: 14657344 
Hcn4tm1(cre/ERT2)Anlu|Hcn4tm1Jsr Hcn4tm1Jsr/Hcn4tm1(cre/ERT2)Anlu
involves: 129S1/Sv * 129X1/SvJ		 MGI:1298209  MP:0003137 abnormal impulse conducting system conduction PMID: 18538341 
Hcn4tm1Rsei Hcn4tm1Rsei/Hcn4tm1Rsei
B6.Cg-Hcn4		 MGI:1298209  MP:0005140 decreased cardiac muscle contractility PMID: 18219271 
Hcn4tm1Rsei Hcn4tm1Rsei/Hcn4tm1Rsei
B6.Cg-Hcn4		 MGI:1298209  MP:0005333 decreased heart rate PMID: 18219271 
Hcn4+|Hcn4tm1Rsei Hcn4tm1Rsei/Hcn4+
B6.Cg-Hcn4		 MGI:1298209  MP:0005333 decreased heart rate PMID: 18219271 
Hcn4tm1(cre/ERT2)Anlu|Hcn4tm1Jsr Hcn4tm1Jsr/Hcn4tm1(cre/ERT2)Anlu
involves: 129S1/Sv * 129X1/SvJ		 MGI:1298209  MP:0005333 decreased heart rate PMID: 18538341 
Hcn4tm1Jsr|Myl2+|Myl2tm1(cre)Krc Hcn4tm1Jsr/Hcn4tm1Jsr,Myl2tm1(cre)Krc/Myl2+
involves: 129/Sv		 MGI:1298209  MGI:97272  MP:0006207 embryonic lethality during organogenesis PMID: 14657344 
Hcn4tm1.1Jsr Hcn4tm1.1Jsr/Hcn4tm1.1Jsr
involves: 129/Sv * C57BL/6		 MGI:1298209  MP:0006207 embryonic lethality during organogenesis PMID: 14657344 
Hcn4tm1Rsei Hcn4tm1Rsei/Hcn4tm1Rsei
B6.Cg-Hcn4		 MGI:1298209  MP:0006207 embryonic lethality during organogenesis PMID: 18219271 
Hcn4+|Hcn4tm1(cre/ERT2)Anlu Hcn4tm1(cre/ERT2)Anlu/Hcn4+
Not Specified		 MGI:1298209  MP:0002169 no abnormal phenotype detected PMID: 18538341 
Hcn4tm1(cre/ERT2)Anlu|Hcn4tm1Jsr Hcn4tm1Jsr/Hcn4tm1(cre/ERT2)Anlu
involves: 129S1/Sv * 129X1/SvJ		 MGI:1298209  MP:0010520 sinoatrial block PMID: 18538341 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Sinus node dysfunction.
Drugs:  Ivabradine.
Side effects:  Not established.
Therapeutic use:  Stable angina pectoris.
References:  1
Mutations not determined
Disease:  Brugada syndrome 8; BRGDA8
OMIM:  613123
Orphanet:  130
References: 
Mutations not determined
Disease:  Sick sinus syndrome 2, autosomal dominant; SS2
OMIM:  163800
Orphanet:  166282, 334
Comments:  Individuals experience a range of symptoms including sick sinus syndrome with AV block [81], sinus node dysfunction with recurrent syncope, QT prolongation, polymorphic ventricular tachycardia and torsade de pointes [79] and sinus bradycardia (40 bpm) with intermittent atrial fibrillation [80].
References:  9,16,23
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human S672R 9
Missense Human D553N 23
Missense Human HCN4-573X 16
Gene Expression and Pathophysiology
1.8-fold elevation of HCN4 mRNA in transgenic mice overexpressing the human β2-adrenoceptor; significant increase of HCN4 mRNA levels in hypertrophied cardiac myocytes.
Tissue or cell type:  Ventricular myocytes.
Pathophysiology:  Cardiac hypertrophy.
Species:  None
Technique: 
References:  4-5
3-fold increase in HCN4 gene expression in end-stage human heart failure.
Tissue or cell type:  Human ventricular myocytes.
Pathophysiology:  Heart failure.
Species:  Human
Technique: 
References:  2

REFERENCES

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1. Baruscotti, M; Bucchi, A; Difrancesco, D. (2005) Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacol. Ther., 107 (1): 59-79. [PMID:15963351]

2. Borlak, J; Thum, T. (2003) Hallmarks of ion channel gene expression in end-stage heart failure. FASEB J., 17 (12): 1592-608. [PMID:12958166]

3. Decher, N; Bundis, F; Vajna, R; Steinmeyer, K. (2003) KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents. Pflugers Arch., 446 (6): 633-40. [PMID:12856183]

4. Fernández-Velasco, M; Goren, N; Benito, G; Blanco-Rivero, J; Boscá, L; Delgado, C. (2003) Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts. J. Physiol. (Lond.), 553 (Pt 2): 395-405. [PMID:14514868]

5. Graf, EM; Heubach, JF; Ravens, U. (2001) The hyperpolarization-activated current If in ventricular myocytes of non-transgenic and beta2-adrenoceptor overexpressing mice. Naunyn Schmiedebergs Arch. Pharmacol., 364 (2): 131-9. [PMID:11534852]

6. Knaus, A; Zong, X; Beetz, N; Jahns, R; Lohse, MJ; Biel, M; Hein, L. (2007) Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine. Circulation, 115 (7): 872-80. [PMID:17261653]

7. Ludwig, A; Zong, X; Stieber, J; Hullin, R; Hofmann, F; Biel, M. (1999) Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J., 18 (9): 2323-9. [PMID:10228147]

8. Michels, G; Er, F; Khan, I; Südkamp, M; Herzig, S; Hoppe, UC. (2005) Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation, 111 (4): 399-404. [PMID:15687126]

9. Milanesi, R; Baruscotti, M; Gnecchi-Ruscone, T; DiFrancesco, D. (2006) Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N. Engl. J. Med., 354 (2): 151-7. [PMID:16407510]

10. Monteggia, LM; Eisch, AJ; Tang, MD; Kaczmarek, LK; Nestler, EJ. (2000) Cloning and localization of the hyperpolarization-activated cyclic nucleotide-gated channel family in rat brain. Brain Res. Mol. Brain Res., 81 (1-2): 129-39. [PMID:11000485]

11. Moosmang, S; Biel, M; Hofmann, F; Ludwig, A. (1999) Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol. Chem., 380 (7-8): 975-80. [PMID:10494850]

12. Müller, F; Scholten, A; Ivanova, E; Haverkamp, S; Kremmer, E; Kaupp, UB. (2003) HCN channels are expressed differentially in retinal bipolar cells and concentrated at synaptic terminals. Eur. J. Neurosci., 17 (10): 2084-96. [PMID:12786975]

13. Qu, J; Altomare, C; Bucchi, A; DiFrancesco, D; Robinson, RB. (2002) Functional comparison of HCN isoforms expressed in ventricular and HEK 293 cells. Pflugers Arch., 444 (5): 597-601. [PMID:12194012]

14. Robinson, RB; Siegelbaum, SA. (2003) Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol., 65: 453-80. [PMID:12471170]

15. Santoro, B; Liu, DT; Yao, H; Bartsch, D; Kandel, ER; Siegelbaum, SA; Tibbs, GR. (1998) Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell, 93 (5): 717-29. [PMID:9630217]

16. Schulze-Bahr, E; Neu, A; Friederich, P; Kaupp, UB; Breithardt, G; Pongs, O; Isbrandt, D. (2003) Pacemaker channel dysfunction in a patient with sinus node disease. J. Clin. Invest., 111 (10): 1537-45. [PMID:12750403]

17. Seifert, R; Scholten, A; Gauss, R; Mincheva, A; Lichter, P; Kaupp, UB. (1999) Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis. Proc. Natl. Acad. Sci. U.S.A., 96 (16): 9391-6. [PMID:10430953]

18. Shi, W; Wymore, R; Yu, H; Wu, J; Wymore, RT; Pan, Z; Robinson, RB; Dixon, JE; McKinnon, D; Cohen, IS. (1999) Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ. Res., 85 (1): e1-6. [PMID:10400919]

19. Stevens, DR; Seifert, R; Bufe, B; Müller, F; Kremmer, E; Gauss, R; Meyerhof, W; Kaupp, UB; Lindemann, B. (2001) Hyperpolarization-activated channels HCN1 and HCN4 mediate responses to sour stimuli. Nature, 413 (6856): 631-5. [PMID:11675786]

20. Stieber, J; Herrmann, S; Feil, S; Löster, J; Feil, R; Biel, M; Hofmann, F; Ludwig, A. (2003) The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc. Natl. Acad. Sci. U.S.A., 100 (25): 15235-40. [PMID:14657344]

21. Stieber, J; Stöckl, G; Herrmann, S; Hassfurth, B; Hofmann, F. (2005) Functional expression of the human HCN3 channel. J. Biol. Chem., 280 (41): 34635-43. [PMID:16043489]

22. Stieber, J; Wieland, K; Stöckl, G; Ludwig, A; Hofmann, F. (2006) Bradycardic and proarrhythmic properties of sinus node inhibitors. Mol. Pharmacol., 69 (4): 1328-37. [PMID:16387796]

23. 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. (2004) Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J. Biol. Chem., 279 (26): 27194-8. [PMID:15123648]

24. Yu, X; Duan, KL; Shang, CF; Yu, HG; Zhou, Z. (2004) Calcium influx through hyperpolarization-activated cation channels (I(h) channels) contributes to activity-evoked neuronal secretion. Proc. Natl. Acad. Sci. U.S.A., 101 (4): 1051-6. [PMID:14724293]

To cite this database page, please use the following:

Martin Biel, Franz Hofmann, U. Benjamin Kaupp.
Cyclic nucleotide-regulated channels: HCN4. Last modified on 23/01/2012. Accessed on 21/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=403.


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