HCN3 | Cyclic nucleotide-regulated channels | IUPHAR/BPS Guide to PHARMACOLOGY

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Target not currently curated in GtoImmuPdb

Target id: 402

Nomenclature: HCN3

Family: Cyclic nucleotide-regulated channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 774 1q22 HCN3 hyperpolarization activated cyclic nucleotide gated potassium channel 3 11
Mouse 6 1 779 3 F2 Hcn3 hyperpolarization-activated, cyclic nucleotide-gated K+ 3 7
Rat 6 1 780 2q34 Hcn3 hyperpolarization-activated cyclic nucleotide-gated potassium channel 3 6
Previous and Unofficial Names
BCNG4 | HAC3 | hyperpolarization activated cyclic nucleotide-gated potassium channel 3 | hyperpolarization-activated, cyclic nucleotide-gated K+ 3 | hyperpolarization-activated
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
HCN1 8
HCN4 8
Auxiliary Subunits
Name References
Kctd3 1
Trip8b 1
Other Associated Proteins
Name References
Not determined
Ion Selectivity and Conductance
Species:  Human
Rank order:  K+ > Na+
References:  11
Ion Selectivity and Conductance Comments
PNa/PK ~ 0.3
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -77.0 1244.0 11 HEK 293 cells. Human
Inactivation  - -
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -95.0 470.0 5 HEK 293 cells. Mouse
Inactivation  - -
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -114.0 - 2 Cardiomyocytes Mouse
Inactivation  - -

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Gating Inhibitor Comments
cAMP and cGMP shift V0.5 of murine HCN3 by -5 mV [5] whereas human HCN3 is not modulated by cAMP [11].
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
cilobradine Hs Antagonist 6.0 pIC50 - -40.0 12
pIC50 6.0 [12]
Holding voltage: -40.0 mV
ivabradine Hs Antagonist 5.7 pIC50 - - 12
pIC50 5.7 (IC50 2.25x10-6 M) [12]
zatebradine Hs Antagonist 5.7 pIC50 - -40.0 12
pIC50 5.7 [12]
Holding voltage: -40.0 mV
ZD7288 Hs Antagonist 4.5 pIC50 - - 11
pIC50 4.5 (IC50 3.4x10-5 M) [11]
Cs+ Hs Antagonist 3.8 pIC50 - -40.0 11
pIC50 3.8 (IC50 1.57x10-4 M) [11]
Holding voltage: -40.0 mV
Tissue Distribution
Fetal brain, adult brain tissues.
Species:  Human
Technique:  Dot-blot analysis.
References:  11
Heart (cardiac atrium and ventricle).
Species:  Mouse
Technique:  RT-PCR and immunohistochemistry.
References:  2
Pelvis-kidney junction.
Species:  Mouse
Technique:  Immunocytochemistry and real-time PCR.
References:  4
Species:  Mouse
Technique:  In situ hybridisation
References:  7
Brain, retina.
Species:  Mouse
Technique:  Western Blot
References:  5
Distal colon.
Species:  Mouse
Technique:  RT-PCR
References:  13
Urinary bladder.
Species:  Rat
Technique:  RT-PCR and Western blot.
References:  3
Species:  Rat
Technique:  Immunohistochemistry
References:  9
Species:  Rat
Technique:  Immunohistochemistry
References:  10
Physiological Consequences of Altering Gene Expression
The knockout of HCN3 results in an increase in the T-wave amplitude caused by an acceleration of the late repolarization phase in epicardial myocytes.
Species:  Mouse
Tissue:  Heart
Technique:  Gene knockout
References:  2


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1. Cao-Ehlker X, Zong X, Hammelmann V, Gruner C, Fenske S, Michalakis S, Wahl-Schott C, Biel M. (2013) Up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by specific interaction with K+ channel tetramerization domain-containing protein 3 (KCTD3). J. Biol. Chem., 288 (11): 7580-9. [PMID:23382386]

2. Fenske S, Mader R, Scharr A, Paparizos C, Cao-Ehlker X, Michalakis S, Shaltiel L, Weidinger M, Stieber J, Feil S et al.. (2011) HCN3 contributes to the ventricular action potential waveform in the murine heart. Circ. Res., 109 (9): 1015-23. [PMID:21903939]

3. He P, Deng J, Zhong X, Zhou Z, Song B, Li L. (2012) Identification of a hyperpolarization-activated cyclic nucleotide-gated channel and its subtypes in the urinary bladder of the rat. Urology, 79 (6): 1411.e7-13. [PMID:22446339]

4. Hurtado R, Bub G, Herzlinger D. (2010) The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis. Kidney Int., 77 (6): 500-8. [PMID:20032965]

5. Mistrík P, Mader R, Michalakis S, Weidinger M, Pfeifer A, Biel M. (2005) The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. J. Biol. Chem., 280 (29): 27056-61. [PMID:15923185]

6. 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]

7. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A. (2001) Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur. J. Biochem., 268 (6): 1646-52. [PMID:11248683]

8. Much B, Wahl-Schott C, Zong X, Schneider A, Baumann L, Moosmang S, Ludwig A, Biel M. (2003) Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels. J. Biol. Chem., 278 (44): 43781-6. [PMID:12928435]

9. 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]

10. Notomi T, Shigemoto R. (2004) Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J. Comp. Neurol., 471 (3): 241-76. [PMID:14991560]

11. 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]

12. 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]

13. Xiao J, Nguyen TV, Ngui K, Strijbos PJ, Selmer IS, Neylon CB, Furness JB. (2004) Molecular and functional analysis of hyperpolarisation-activated nucleotide-gated (HCN) channels in the enteric nervous system. Neuroscience, 129 (3): 603-14. [PMID:15541882]


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How to cite this page

Martin Biel, Verena Hammelmann.
Cyclic nucleotide-regulated channels: HCN3. Last modified on 10/03/2017. Accessed on 19/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=402.