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FLASH GENE

Symbol

HCN4

contributors: mct/npt - updated : 17-03-2017

HGNC name	hyperpolarization activated cyclic nucleotide-gated potassium channel 4
HGNC id	16882

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	BRGS8 Brugada syndrome 8 FSBD familial sinusal bradycardia
Location	15q24.1      Physical location : 73.612.200 - 73.661.605
Synonym name	potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4
Synonym symbol(s)	SSS2

DNA

TYPE	functioning gene
STRUCTURE	49.41 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005477 8 - 7245 NP_005468 - 1203 - 2002 12194012

EXPRESSION

Type

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart atrium       Homo sapiens Adult   heart ventricle       Homo sapiens Adult Nervous brain diencephalon thalamus   predominantly Mus musculus   brain hindbrain cerebellum     Rattus norvegicus Reproductive male system testis       Visual eye retina       Rattus norvegicus

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum cardiac     Homo sapiens

cells

System Cell Pubmed Species Stage Rna symbol Muscular myocyte Homo sapiens Nervous Purkinje cell Rattus norvegicus

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N terminus is important for HCN4 channel activation
	six transmembrane segments
	a pore helix and a selectivity filter between S5 and S6
	a caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins
	a cyclic nucleotide binding domain (CNBD) in the C terminus (likely S4 acting as the voltage gated sensor

mono polymer

homomer , heteromer , dimer

HOMOLOGY

Homologene

FAMILY	potassium channel HCN family
	superfamily of voltage-gated pore loop channels

CATEGORY

transport channel

SUBCELLULAR LOCALIZATION

plasma membrane

basic FUNCTION	playing a critical role in shaping the autonomous activity of single neurons and the periodocity of network oscillations
	playing a key role in automaticity of sinus node in the heart
	inward current activated by hyperpolarization from the resting potential and an important modulator of action potential firing frequency in many excitable cells (Momin 2008)
	hyperpolarization-activated nucleotide-gated channel playing a major role in the diastolic depolarization of sinus atrial node cells (Nof 2007)
	plays a key role in the control of cardiac and neuronal rhythmicity ("pacemaker current") and contributes to several other neuronal processes, including determination of resting membrane potential, dendritic integration and synaptic transmission (Wahl-Schott 2009)
	HCN4 was confirmed as the predominant isoform of the primary pacemaker followed by a distinct expression of HCN1, but in contrast HCN2 shows only a confined expression to individual pacemaker cells
	HCN1, HCN2, and HCN4 subunits may have distinct physiological roles in the developing hippocampus
	HCN1, HCN2, HCN4 channels are important regulators of excitability in neural, cardiac, and other pacemaking cells, which are often altered in disease

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	THY1 colocalizes and coimmunoprecipitates potentially with a membrane-spanning protein HCN4 in retina
	IRX6 is likely required for the correct axon stratification of HCN4-expressing cells within the OFF sublamina of the inner plexiform layer
	developmental change in HCN4-CAV3 association in human embryonic stem cell-derived cardiomyocytes (hESC-CM)
	TRPM7 influences diastolic membrane depolarization and automaticity in sinoatrial node (SAN) indirectly via regulation of HCN4 expression

cell & other

REGULATION

activated by

hyperpolarization-activated and cyclic nucleotide gated potassium

ASSOCIATED DISORDERS

corresponding disease(s)

FSBD , BRGS8

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation     loss of function with sinus nodal dysfunction, QT prolongation and polymorphic ventricular tachycardia

Susceptibility

to Atrial fibrillation (AF)

Variant & Polymorphism other	HCN4 haploinsufficiency is the likely mechanism for early-onset AF in the p.Pro257Ser carrier

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS