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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
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
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
8 - 7245 - 1203 - 2002 12194012
EXPRESSION
Type
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Cardiovascularheartatrium    Homo sapiensAdult
 heartventricle    Homo sapiensAdult
Nervousbraindiencephalonthalamus predominantly Mus musculus
 brainhindbraincerebellum   Rattus norvegicus
Reproductivemale systemtestis   
Visualeyeretina    Rattus norvegicus
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Muscularstriatumcardiac   Homo sapiens
cells
SystemCellPubmedSpeciesStageRna symbol
Muscularmyocyte Homo sapiens
NervousPurkinje 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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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