Description: hyperpolarization activated cyclic nucleotide-gated potassium channel 2
Gene: Hcn2     Synonyms: HCN2, HAC1, BCNG2, ih2

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HCN channels are voltage-gated ionic channels, regulated by cyclic nucleotides, such as cyclic adenosine-mono-phosphate (cAMP). 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]

See [457] for a comprehensive introduction.



RGD ID Chromosome Position Species
620689 7 11485257-11503614 Rat
732306 10 79179379-79198853 Mouse
732305 19 589893-617159 Human

Hcn2 : hyperpolarization activated cyclic nucleotide-gated potassium channel 2



Acc No Sequence Length Source
NM_053684 n/A n/A NCBI
NM_008226 n/A n/A NCBI
NM_001194 n/A n/A NCBI



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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]


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]


The transmembrane protein KCR1 reduces HCN2 current densities and affects single- channel current parameters of this channel. [457]

Filamin A

HCN1 (but not HCN2 or HCN4) binds filamin A, a putative cytoplasmic scaffold protein that binds actin. It causes clustering and slows down activation and deactivation kinetics of HCN1. [457]


Disruption of lipid rafts by cholesterol depletion caused a redistribution of HCN channels and thus influenced their kinetics.[460]



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HCN1 Cartoon of the HCN2 channel illustrating epilepsy associated amino acid variation, proposed TRIP8b binding sites and predicted proteolytic truncation in the C-terminus of the cardiac channel [1696]

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]



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Expression of HCN2 in CNS

HCN2 is distributed nearly ubiquitously, with the highest expression in the thalamus, brainstem nuclei and small nociceptive DRG neurons [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]

HCN2 is distributed nearly ubiquitously throughout most brain regions, with the highest expression in the thalamus and brain stem nuclei. [457]

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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]

The role of HCN channels in the following processes has been studied: dendritic integration, working memory, constraining hippocampal LTP, motor learning , synaptic transmission, resonance and oscillations, the generation of thalamic rhythms, generation of cardiac rythmicity. [457]



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. [2



Model HCN2 (ID=10)       Edit

CellType Dorsal root ganglion
Age 21 Days
Reversal -45.0 mV
Ion Hcn +
Ligand ion
Reference [57] S Moosmang et. al; Eur. J. Biochem. 2001 Mar
mpower 1.0
m Inf 1.0000/(1+exp((v- -99)/6.2))
m Tau 184.0000

MOD - xml - channelML



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).


Biel M et al. Hyperpolarization-activated cation channels: a multi-gene family.
Rev. Physiol. Biochem. Pharmacol., 1999 , 136 (165-81).


Giorgetti A et al. A homology model of the pore region of HCN channels.
Biophys. J., 2005 Aug , 89 (932-44).


Park K et al. HCN channel activity-dependent modulation of inhibitory synaptic transmission in the rat basolateral amygdala.
Biochem. Biophys. Res. Commun., 2011 Jan 28 , 404 (952-7).


Biel M et al. Hyperpolarization-activated cation channels: from genes to function.
Physiol. Rev., 2009 Jul , 89 (847-85).


Barbuti A et al. Localization of pacemaker channels in lipid rafts regulates channel kinetics.
Circ. Res., 2004 May 28 , 94 (1325-31).

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

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

Reid CA et al. HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications.
Br. J. Pharmacol., 2012 Jan , 165 (49-56).

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Contributors: Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite this page: [Contributors] Channelpedia , accessed on [date]