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FLASH GENE

Symbol

HCN2

contributors: mct/npt/pgu - updated : 18-03-2019

HGNC name	hyperpolarization activated cyclic nucleotide-gated potassium channel 2
HGNC id	4846

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type	restricted

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         Hearing/Equilibrium ear inner cochlea     Homo sapiens Nervous brain hindbrain cerebellum     Rattus norvegicus

tissue

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

cells

System Cell Pubmed Species Stage Rna symbol Hearing / Equilibrium hair cell receptor Homo sapiens Hearing / Equilibrium stereocilia Homo sapiens Muscular myocyte Nervous Purkinje cell Rattus norvegicus

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	six transmembrane segments
	a leucine zipper of HCN channels that is a major determinant for hyperpolarization-activated channel gating
	a pore helix and a selectivity filter between S5 and S6 and a cyclic nucleotide binding domain in the C terminus

HOMOLOGY

Homologene

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

CATEGORY

transport channel

SUBCELLULAR LOCALIZATION

plasma membrane

basic FUNCTION	pace-maker channel of the heart
	inward current activated by hyperpolarization from the resting potential and an important modulator of action potential firing frequency in many excitable cells
	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
	both the HCN1 and HCN2 isoforms are predominantly N-glycosylated in the embryonic heart, where they are found in significant amounts and where HCN-mediated currents are known to regulate beating frequency
	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
	HCN2 channel activity reduces the repolarization reserve of the ventricular action potential and increases ectopic automaticity under pathological conditions such as excessive beta-adrenergic stimulation
	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
	HCN2 channel may play an important role in regularizing firing patterns of subthalamic nucleus (STN) neurons, which is critical for basal ganglia motor functions
	HCN2 channel may hold an essential position in normal rhythm patterns of STN neuronal firing activity and subsequent motor function of basal ganglia

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

part of HCN channel ((HCN1 and HCN2 may coassemble to form heteromeric channels in some areas, similar to other K(+) channels)

INTERACTION

DNA

RNA

small molecule

protein

neuropathic pain is initiated by HCN2-driven action potential firing in SCN10A-expressing nociceptors

cell & other

REGULATION

activated by

hyperpolarization-activated and cyclic nucleotide gated potassium

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation     gain of function in Genetic generalized epilepsy (GGE) constitutional     --over   in chronic inflammation resulting in an increased expression of HCN2 and causing sensitization in peripheral and spinal terminals of the pain transduction pathway constitutional germinal mutation       contributes to febrile seizures by shifting the channel's kinetics in a temperature-dependent manner

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed miscelleaneous pain   HCN2-selective blockers may have value as analgesics to combat both inflammatory and neuropathic pain neurology neurodegenerative alzheimer silencing or inhibition of HCN2 affects APP processing and thereby could serve as a potential treatment strategy

ANIMAL & CELL MODELS

mutation in HCN2 likely leads to impaired gastrointestinal motility, causing the severe growth restriction seen in mice with mutations that eliminate HCN2 expression