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hyperpolarization-activated cyclic nucleotide-gated potassium channel 1
Synonyms: HCN1 BCNG1 HAC-2 BCNG-1, ih1. Symbol: Hcn1


The hyper polarization-activated cyclic nucleotide-gated (HCN) Channels belong to the superfamily of pore-loop cation channels. In mammals the HCN channel family comprises of 4 members (HCN1-4) that are expressed in the heart and nervous system. HCN channels are activated by membrane hyper polarization, are permeable to Na+ and K+ and are constitutively open at voltages near the resting membrane potential [1690]. In contrast to most Na+ and K+ ionic channels, which open when membrane potential is depolarized, they are opened when the membrane potential hyperpolarizes below -50 mV. [455]


Hcn1 : hyperpolarization-activated cyclic nucleotide-gated potassium channel 1

RGD ID Chromosome Position Species
620688 2 49525949-49939066 Rat
733931 13 118391127-118769835 Mouse
733930 5 45259352-45696220 Human


Acc No Sequence Length Source
NM_053375 NCBI
NM_010408 NCBI
NM_021072 NCBI


Accession Name Definition Evidence
GO:0030425 dendrite A neuron projection that has a short, tapering, often branched, morphology, receives and integrates signals from other neurons or from sensory stimuli, and conducts a nerve impulse towards the axon or the cell body. In most neurons, the impulse is conveyed from dendrites to axon via the cell body, but in some types of unipolar neuron, the impulse does not travel via the cell body. 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:0030424 axon The long process of a neuron that conducts nerve impulses, usually away from the cell body to the terminals and varicosities, which are sites of storage and release of neurotransmitter. IEA
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


MinK-related peptide 1 encoded by KCNE2

HCN isoforms in the CHO cell system exposed to MinK-related peptide 1 at whole cell level and single cell level:

On the whole-cell level:

Current densities of all HCN isoforms were significantly increased by KCNE2 without altering voltage dependence or current reversal. All HCN subtypes displayed faster activation kinetics upon co-expression with KCNE2.

Single-channel level:

KCNE2 expression increased amplitudes and conductance of HCN1, HCN2 and HCN4 significantly. Mean open time was significantly increased in cells co-expressing HCN2+KCNE2, while it was unaffected in HCN1+KCNE2 and reduced in HCN4+KCNE2 co-transfected cells compared to the respective HCN subunits alone. [54]


Coexpression of HCN1 and HCN2 yields Ih currents that activate with kinetics and a voltage dependence that tend to be intermediate between those of HCN1 and HCN2 homomers, although the coexpressed channels do show a relatively large shift by cAMP (+14 mV). Neither the kinetics, steady-state voltage dependence, nor cAMP dose–response curve for the coexpressed Ih can be reproduced by the linear sum of independent populations of HCN1 and HCN2 homomers [1697]


Lidocaine inhibited HCN1, HCN2, HCN1-HCN2 and HCN4 channel currents at 100 μM in both oocytes and/or HEK293 cells; it caused a decrease in both tonic and maximal current (~30 to 50% inhibition) and slowed current activation kinetics for all subunits. Lidocaine evoked a hyperpolarizing shift in half-activation voltage but only for HCN1 and HCN1-HCN2 channels. [459]


Several molecules were developed to block the pacemaker channels, such as alinidine, cilobradine, zatebradina, ivabradine and ZD7288, but only ivabradine (a benzocyclobutane compound) has passed all the clinical trials and is currently marketed as an anti-anginal drug in different states, under the trade name of Procoralan




The HCN channels form the subgroup of cyclic nucleotide-gated cation channel within the large superfamily of the pore loop cation channels. Like other pore loop channels, HCN channels are complexes consisting of 4 subunits that are arranged around the ventral pore. Each HCN channe subunit consists of 3 principal structural ovules: the transmembrane core and the cystosolic amino (N) terminal and carboxyl © terminal domains. The transmembrane core is comosed of 6 transmembrane segments (S1-S6) including a positively charged voltage sensor (S4) and the ion conducting pore region between (S5 and S6. The proximal portion of the systolic C-terminal domain contains the cyclic nucleotide binding domain (CNBD), which mediates modulation by cyclic nucleotides. A highly conserved asparagine residue in the extracellular loop between S5 and the pore loop is glycosylated; this posttranstional channel modification is crucial for normal cell surface expression [1690]


HCN1 2Fo−Fc electron density map showing Hcn1. The N‐terminus of Hcn1 is well ordered, and the N‐acetyl‐Met group is well defined [1691]

Kv1.1 N‐terminal region of Hcn1 is shown in cyan with Cut9 shown as a surface representation, with secondary structure indicated [1691]

The crystal structure of Schizosaccharomyces pombe Cut9 (Cdc16/Apc6) in complex with Hcn1 (Cdc26), showing that Cdc16/Cut9 is a contiguous TPR superhelix of 14 TPR units. A C‐terminal block of TPR motifs interacts with Hcn1, whereas an N‐terminal TPR block mediates Cdc16/Cut9 self‐association through a homotypic interface. The acetylated N‐terminal Met residue of Hcn1 is enclosed within a chamber created from the Cut9 TPR superhelix. Thus, in complex with Cdc16/Cut9, the N‐acetyl‐Met residue of Hcn1, a putative degron for the Doa10 E3 ubiquitin ligase, is inaccessible for Doa10 recognition, protecting Hcn1/Cdc26 from ubiquitin‐dependent degradation [1691]

Similarity in structure to KcsA

A model of the pore of HCN channels, based on the following assumptions, matched well with experiments: In the closed state, the topology of the inner pore of HCN channels is similar to that of K1 channels. In particular, the orientation of the S5 and S6 helices of HCN channels is very similar to that of the corresponding helices of the K1 KcsA and K1 KirBac1.1 channels. In the open state, the S6 helix is bent further than it is in the closed state. [455]


Cellular Distribution in Neuron

HCN channels are expressed in dendrites and axon terminals, in some cases with a heterogeneous distribution [1690]](#a1690)

A graded distribution of HCN1 in apical dendrites of hippocampal, subicular and neocortical layer-5 pyramidal cells was found. A 60-fold increase in HCN1 channel density from somatic to distal apical dendritic membranes, distal dendritic shafts had 16 times more HCN1 labeling than proximal dendrites of similar diameters, and at the same distance from the soma, the density of HCN1 was significantly higher in dendritic shafts than in spines. [324]


Expression of HCN1 in CNS

HCN1 is expressed in the neocortex, hippocampus, brainstem, spinal cord and dorsal root ganglion [1690]

The hyperpolarization-activated cation current If/Ih - and thus associated HCN channels - has been identified in various regions of the mammalian heart, the brain, the peripheral nervous system and the eye. [454]

In the murine sinoatrial node, HCN4 is the most prominently expressed HCN channel, whereas HCN2 and HCN1 are detected there at moderate and low levels, respectively. Retinal photoreceptors express high levels of HCN1, whereas HCN2, 3 and 4 were not found in these cells. In dorsal root ganglion neurons, the dominant HCN transcript is HCN1, followed by HCN2. [57]



HCN channels have a major role in controlling neuronal excitabilitym dendrite inegrationof synaptic potentials, synaptic transmission, and rythmic oscillatory activityin individual neurons and neuronal networks [1690] HCN channel activity can modulate the GABAergic synaptic transmission in the basolateral amygdala, which in turn control the amygdala-related emotional behaviors such as anxiety.[456]


HCN channels’ main function is the generation of the sinus rhythm and, therefore, heart rate control. It should be expected that dysfunction in funny channels would cause arrhythmic behaviour. Molecular approaches have tried to clarify the relationships between mutations of the HCN channels genes and alterations in the cardiac function, above all according to a simple arrhythmic level [1693]

Retinal Function

the impact of HCN1 channels on the retinal functional properties was presented. HCN1 channel loss led to an intensity-dependent prolongation of the rod system response, in agreement with the threshold mechanism of activation of the channel [1692]


Comparison of HCN1 and HCN2 Kinetics

HCN1 HCN1 and HCN2, isoforms coexpressed in neocortex and hippocampus that differ markedly in their biophysical properties, coassemble to generate heteromultimeric channels with novel properties. When expressed in Xenopus oocytes, HCN1 channels activate 5–10-fold more rapidly than HCN2 channels. HCN1 channels also activate at voltages that are 10–20 mV more positive than those required to activate HCN2. In cell-free patches, the steady-state activation curve of HCN1 channels shows a minimal shift in response to cAMP (+4 mV), whereas that of HCN2 channels shows a pronounced shift (+17 mV). [1697]

All four HCN channels, HCN1-4, measured in transfected HEK293 cells, exhibit very similar half maximal activation potentials. In contrast, the channels displayed considerable differences in their activation rates in the order HCN1 > HCN2 > HCN3 > HCN4. [57]


[1] HCN1 (Model ID = 9)

AnimalMouse 52
CellType Dorsal root ganglion
Age 21 Days
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- -94)/8.1))
mTau 30.0000

MOD xml channelML


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Contributors : Rajnish Ranjan, Michael Schartner, Nitin Khanna

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