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HCN3

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Target id: 402

Nomenclature: HCN3

Family: Cyclic nucleotide-regulated channels (CNG)

Contents:

Gene and Protein Information Click here for help
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 F1 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 Click here for help
BCNG4 | HAC3 | hyperpolarization activated cyclic nucleotide-gated potassium channel 3 | hyperpolarization-activated, cyclic nucleotide-gated K+ 3 | hyperpolarization-activated
Database Links Click here for help
Alphafold Q9P1Z3 (Hs), O88705 (Mm), Q9JKA8 (Rn)
CATH/Gene3D 2.60.120.10
ChEMBL Target CHEMBL1795173 (Hs)
Ensembl Gene ENSG00000143630 (Hs), ENSMUSG00000028051 (Mm), ENSRNOG00000020444 (Rn)
Entrez Gene 57657 (Hs), 15168 (Mm), 114245 (Rn)
Human Protein Atlas ENSG00000143630 (Hs)
KEGG Gene hsa:57657 (Hs), mmu:15168 (Mm), rno:114245 (Rn)
OMIM 609973 (Hs)
Pharos Q9P1Z3 (Hs)
RefSeq Nucleotide NM_020897 (Hs), NM_008227 (Mm), NM_053685 (Rn)
RefSeq Protein NP_065948 (Hs), NP_032253 (Mm), NP_446137 (Rn)
UniProtKB Q9P1Z3 (Hs), O88705 (Mm), Q9JKA8 (Rn)
Wikipedia HCN3 (Hs)
Associated Proteins Click here for help
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 Click here for help
Species:  Human
Rank order:  K+ > Na+
References:  11
Ion Selectivity and Conductance Comments
PNa/PK ~ 0.3
Voltage Dependence Click here for help
  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  - -

Download all structure-activity data for this target as a CSV file go icon to follow link

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
Holding voltage (mV)
Reference
cilobradine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.0 pIC50 - -40.0 12
⤷ pIC50 6.0 [12]
Holding voltage: -40.0 mV
ivabradine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 5.7 pIC50 - - 12
⤷ pIC50 5.7 (IC50 2.25x10-6 M) [12]
zatebradine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.7 pIC50 - -40.0 12
⤷ pIC50 5.7 [12]
Holding voltage: -40.0 mV
ZD7288 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 4.5 pIC50 - - 11
⤷ pIC50 4.5 (IC50 3.4x10-5 M) [11]
Cs+ Click here for species-specific activity table Hs Antagonist 3.8 pIC50 - -40.0 11
⤷ pIC50 3.8 (IC50 1.57x10-4 M) [11]
Holding voltage: -40.0 mV
Tissue Distribution Click here for help
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
Retina.
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
Retina.
Species:  Rat
Technique:  Immunohistochemistry
References:  9
Brain.
Species:  Rat
Technique:  Immunohistochemistry
References:  10
Physiological Consequences of Altering Gene Expression Click here for help
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

References

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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]

Contributors

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How to cite this page

Becirovic E, Biel M, Fenske S, Hammelmann V, Hofmann F, Kaupp UB. Cyclic nucleotide-regulated channels (CNG) in GtoPdb v.2023.1. IUPHAR/BPS Guide to Pharmacology CITE. 2023; 2023(1). Available from: https://doi.org/10.2218/gtopdb/F71/2023.1.