HCN4

Description: hyperpolarization activated cyclic nucleotide-gated potassium channel 4
Gene: Hcn4 Synonyms: HCN4, Hac3, HCN3, Bcng4, BCNG-4, ih4

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Introduction

Experimental data

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Gene

RGD ID	Chromosome	Position	Species
71065	8	62629828-62667248	Rat
737127	9	58671319-58708762	Mouse
737126	15	73612200-73661605	Human

Hcn4 : hyperpolarization activated cyclic nucleotide-gated potassium channel 4

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Transcript

Acc No	Sequence	Length	Source
NM_021658	n/A	n/A	NCBI
NM_001081192	n/A	n/A	NCBI
NM_005477	n/A	n/A	NCBI

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Ontology

Accession	Name	Definition	Evidence
GO:0016021	integral to membrane	Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane.	IEA
GO:0016020	membrane	Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins.	IEA
GO:0043195	terminal button	Terminal inflated portion of the axon, containing the specialized apparatus necessary to release neurotransmitters. The axon terminus is considered to be the whole region of thickening and the terminal button is a specialized region of it.	IDA

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Interaction

MUTATION

A missense mutation (S672R) on the exon 7 in hHCN4 gene induces the production of an isoform of the pacemaker channel changed at cAMP binding site level: this was responsible for a familial form of an asymptomatic bradycardia.

A mutation in the exon 5 of the HCN4 gene is functionally related to a truncated protein, unable to bind cAMP and, therefore, presenting a dominant negative effect on channel function. [1693]

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Protein

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Structure

CARTOON REPRESENTATION OF HCN CHANNEL TOPOLOGY

One of the four subunits is depicted here. A subunit is composed of six transmembrane domains (S1–S6). S4, the putative voltage sensor, is characterized in all four HCN subunits by the presence of 11 basic residues (2 lysines, 7 arginines, and 2 histidines) within its domain and in the close vicinity. Also drawn are the domains involved in cyclic nucleotide binding (CNBD) in the C-terminus and the cAMP molecule.

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Distribution

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Expression

Expression of HCN1 in CNS

HCN4 is strongly expressed in the thalamic nuclei and the olfactory bulb [690]

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Functional

DISEASE

Missense mutations on the exon 5 of the HCN4 gene have been found in a Japanese family suffering from sick sinus syndrome, recurrent syncopes, severe bradycardia (39 bpm), long QT interval and polymorphic ventricular tachycardia [1693]

FUNCTION BY KNOCK-OUT

Recently a knock-out HCN mice model was developed in order to study the influence of the HCN4 isoform in pacemaker generation and rate control. It demonstrated a severe bradycardia (about 50% respect of original rate) and atrio-ventricular block in a mouse model in which HCN4 was ablated. Furthermore, a 70% in If-current was outlined in the same models with an overall reduction of the spontaneous rate of about 60%. These results confirmed the essential role of HCN4 in adult mice in controlling the impulse generation and conduction of heart impulse [1693]

Embryonic mice carrying this deletion died between embryonic days 9.5 and 11.5 due to lack of cardiac pacemaking. In this respect, it is relevant to note that cardiac development is complete at about the same time indicating that the lack of HCN4-dependent pacemaking is incompatible with a correct cardiogenesis and with embry- odic survival [1694]

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Kinetics

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Model

[1] HCN4 (Model ID = 12)

Animal	Mouse
CellType	Dorsal root ganglion
Age	21 Days
Temperature	0.0°C
Reversal	-45.0 mV
Ion	Hcn +
Ligand ion
Reference	S Moosmang et. al; Eur. J. Biochem. 2001 Mar
mpower	1.0
mInf	1.0000/(1+exp((v- -100)/9.6))
mTau	461.0000

MOD - xml - channelML

References

Brandt MC et al. Effects of KCNE2 on HCN isoforms: distinct modulation of membrane expression and single channel properties.
Am. J. Physiol. Heart Circ. Physiol., 2009 Jul , 297 (H355-63).

Moosmang S et al. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues.
Eur. J. Biochem., 2001 Mar , 268 (1646-52).

1690

Benarroch EE HCN channels: function and clinical implications.
Neurology, 2013 Jan 15 , 80 (304-10).

1693

Scicchitano P et al. HCN channels and heart rate.
Molecules, 2012 , 17 (4225-35).

1694

Baruscotti M et al. HCN-related channelopathies.
Pflugers Arch., 2010 Jul , 460 (405-15).

1695

Baruscotti M et al. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4.
Proc. Natl. Acad. Sci. U.S.A., 2011 Jan 25 , 108 (1705-10).

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Credits

Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/ionchannels/64/ , accessed on [date]