Channelpedia

HCN1

Description: hyperpolarization-activated cyclic nucleotide-gated potassium channel 1
Gene: Hcn1
Alias: HCN1, BCNG1, HAC-2, BCNG-1, ih1

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Introduction

HCN1, encoded by the gene hcn1, is a hyperpolarization-activated cyclic nucleotide-gated potassium channel. HCN1 is widely expressed throughout the body, though it is highest in certain areas of the central nervous system. It is involved in the generation of the I(h) current which controls neuron excitability.

Experimental data

Rat HCN1 gene in CHO host cells

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Mouse HCN1 gene in CHO host cells

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Human HCN1 gene in CHO host cells

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Gene

hcn1 is the coding gene for HCN1. In humans, hcn1 is located on chromosome 5p12 and is made up of 8 exons, all of which are coding.

Species NCBI gene ID Chromosome Position
Human 348980 5 441432
Mouse 15165 13 378708
Rat 84390 2 403931
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Transcript

To date, no transcript variants for hcn1 have been identified.

Species NCBI accession Length (nt)
Human NM_021072.4 9933
Mouse NM_010408.3 7911
Rat NM_053375.1 2807
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Protein Isoforms

The human HCN1 protein is composed of 890 amino acids (aa) and has a molecular weight of ~99 Kda.

To date, no isoforms resulting from alternative splicing have been identified.

Species Uniprot ID Length (aa)
Human O60741 890
Mouse O88704 910
Rat Q9JKB0 910

Isoforms

Transcript
Length (nt)
Protein
Length (aa)
Variant
Isoform
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Post-Translational Modifications

Like most mammalian proteins, HCN1 is subject to a series of post translational modifications (PTM).

HCN1 is subject to phosphorylation by various kinases. For instance, phosphorylation by phospholipase C–protein kinase C (PKC) leads to a decrease in HCN current and a reduction in the surface expression of HCN1 [2293]. Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKII) activity is crucial for the proper dendritic localization of HCN1 subunits. The activation of CaMKII, triggered by upstream Ca2+ influx, results in an increase in the surface expression of HCN1 channels and a higher density of I(h) current [2295]

HCN1 undergoes ubiquitination by the Nedd4-2. This ubiquitination process results in a decrease in the cell surface expression and translocation of HCN1, ultimately leading to a loss of function in the Ih current.[2293]

HCN1, like other HCN isoforms, was also found to be S-palmitoylated in HEK293 cell experiments. However, the effects of S-palmitoylation on HCN1 have not yet been elucidated [2298].

PTM
Position
Type
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Structure

HCN1
Visual Representation of HCN1 Structure
Methodology for visual representation of structure available here

The structure of human HCN1 was resolved via cryo-electron microscopy to an overall resolution of 3.5 angstroms, giving us a detailed insight to the channel’s architecture. [2299] Structural resolution of the ion channel highlighted a number of HCN1 specific features:

  • HCN is ∼100 Å in length and ∼75 Å in width
  • The S4–S5 linker is much shorter and not α-helical
  • The gate of HCN1 is closed by a tightly packed inner helical bundle that constricts the pore to a radius of about 1 Å
  • The S4 helix is very long, containing two additional helical turns on the cytoplasmic side. The extension brings the S4–S5 linker into contact with the * C-linker of a neighboring subunit. This feature may allower the channel to stabilize a closed pore when the voltage is depolarized

The structure of the C-terminal region and changes to this area are thought to be responsible for the impact of cAMP binding to HCN channels. In the absence of cAMP, the C-terminal region is thought to exert a tonic inhibition on the pore when the C-linker and CNBD domains are in a non-tetrameric form [2303]. When the cAMP concentration increases, the C-linker/CNBD region tetramerizes and releases the inhibition from the pore gate. HCN1's C-terminal domain forms tetramers even at basal cAMP concentrations, in contrast to HCN2 and HCN4, which require saturating cAMP levels for tetramerization. This inherent tetramerization in HCN1 results in a weaker response to increased cAMP. [2304] [2304]

HCN1 predicted AlphaFold size

Species Area (Å2) Reference
Human 5890.08 source
Mouse 7209.19 source
Rat 6853.49 source

Methodology for AlphaFold size prediction and disclaimer are available here

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Kinetics

HCN1 stands out as the HCN family member with the fastest kinetics. Its activation kinetics range from 30 to 300 milliseconds at voltage levels spanning from -140 to -95 mV. Additionally, HCN1 exhibits the most positive V1/2 value, typically falling within the range of -70 to -90 mV, and initiates activation at voltages approximately 20 mV more positive than HCN2 channels.[457] [2304]

HCN1 channels behave similarly as spHCN channels with respect to voltage hysteresis behavior and mode shift. [457]

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Biophysics

Single channel unitary conductance

Single channel unitary conductance is determined experimentally.
For HCN1, there have been recordings of single channel unitary conductance values with some degree of variance between experiments: 0.5 pS [2293]

Models

Model HCN1 (ID=9)      

AnimalMouse
CellType Dorsal root ganglion
Age 21 Days
Temperature0.0°C
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- -94)/8.1))
m Tau 30.0000

MOD - xml - channelML

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Expression and Distribution

Cellular & Tissue

HCN1’s distribution is characterized by its very high and relatively restricted expression in both the central and peripheral nervous system [2306].

In the CNS, these areas are:

Within these various regions, HCN1 levels can vary greatly. HCN1 mRNA expression was demonstrated to be at least eightfold higher in cortical neurons than subcortical neurons [2309]. Two neuronal classes stand out for their exceptionally high HCN1 levels: cortical pyramidal neurons and parvalbumin-positive (PV+) interneurons (basket cells) in the cortex and cerebellum.[2306]

HCN1 was also identified in the PNS. Identified areas include:

  • Nucleus laminaris (NL) region [2310]
  • A-type neurons [2311]
  • Mechanosensitive terminals of myelinated sensory fibers [2311]
  • Large neurons I(h) [2312]
  • Atrioventricular node of the heart [457]

For a more detailed map immunohistochemical localisation of HCN4, please consult the following paper [323]

Developmental

HCN1 was identified at low levels in early development (P1 and P5) but steadily increased by P20. [2313] [2314] Indeed, HCN1 experiences a number of changes in not only its expression but also its distribution over the course of development. In rodents, HCN1 channels tend to shift to dendrites soon after birth. In certain regions, like the hippocampus, HCN1 first appears in the axon terminals but disappears as maturity sets in. These changes in distribution are mediated by accessory proteins involved in channel trafficking [2295].

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CNS Sub-cellular Distribution

The subcellular localization of HCN channels is neuron-type-specific. It is therefore difficult to generalize and pinpoint the exact cellular locations of these channels.

In hippocampal and cortical pyramidal cells, HCN1 can be found in the distal dendrites. In other pyramidal neurons, HCN1 is also located in the somata, albeit at a lower density than that in distal dendrites. [2307] Quantitative analysis revealed a 60-fold increase in the presence of HCN1 channels from somatic to distal apical dendritic membranes. Moreover, distal dendritic shafts exhibited 16 times more HCN1 labeling compared to proximal dendrites with similar diameters. Additionally, at the same distance from the cell body, the density of HCN1 channels was significantly higher in dendritic shafts than in dendritic spines.[324]

In the interneurons of medial septum, hippocampus and cerebellum, HCN1, along with other HCN channels, are expressed at somatic and axonal regions [2295] [321]. HCN1 has also been found present at axonal terminals and preterminal axons of hippocampal basket cells. [2306] In cerebellar basket cells, HCN1 is present at a low density in the somato-dendritic regions but is present at slightly higher density in axon terminals. [321] The presence of HCN1 channels in synaptic terminals, both excitatory and inhibitory if thought to regulate basal glutamatergic synaptic release, impacting overall synaptic transmission. [2307]

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Function

Learning and memory

Deletion of HCN1 has been demonstrated to result in notable impairments in motor skills and memory tasks. Targeted knock-out experiments conducted in Purkinje cerebellar cells have highlighted the stabilizing role of HCN1 within these cells. HCN1 plays a critical role in maintaining the reliable encoding of information and the accurate decoding of input patterns, contributing to proper motor function and memory processes. [457] [2315]

HCN1's contribution to learning and memory is further demonstrated through region-specific knockout experiments. HCN1 deletion from forebrain neurons was shown to have a profound effect on hippocampal-dependent learning and memory processes. This manipulation amplifies theta oscillations and boosts long-term potentiation (LTP) specifically at the input to the distal dendrites of CA1 pyramidal neurons. The underlying mechanism for this influence on learning is attributed to HCN1's regulatory role in the dendritic integration of distal synaptic inputs within pyramidal cells.[2316] [457]

Nociception

HCN1 is thought to contribute to nociception as blockade of the channel via inhibitors was shown to decrease light hypersensitivity in rat model experiments. [2317] Indeed, genetic deletion or pharmacological inhibition of HCN1 generally provides partial analgesia to certain types of neuropathic pain, such as cold hypersensitivity in most animal pain models [2318] [2312]

Channelopathies

HCN1 have been associated with a number of pathologies with epilepsy being the most common channelopathy associated with deregulation of the channel [2319]. Conditions include different gain of function and loss of function epilepsy types, like common forms but also others such as intractable epileptic encephalopathy, temporal lobe epilepsy and absence seizures [2320] [2321] [2322]

HCN1 is also thought to impact affective disorders. HCN1 knockout mice displayed antidepressant-like behavior, highlighting the potential role of HCN1 as a target for anxiety and depression disorders. [2323]

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Interaction

Heteromeric channels

However, there is evidence that certain HCN channels, coexpressed in the same regions, coassemble to generate heteromultimeric channels. For example, HCN1 can be found in conjunction with HCN2, HCN3, and HCN4 in certain areas, leading to the formation of hybrids consisting of both HCN1 and HCN2/HCN3/HCn4 subunits. These heteromultimeric isoforms of HCN channels exhibit I(h) currents with activation kinetics and voltage dependence that tend to fall in between those of the "parent" homomers. These heteromers also display a relatively large shift by cAMP (+14 mV) [1697] [2296].

HCN1, like other channels, is regulated by various auxiliary proteins and secondary messengers. These regulatory proteins play important roles in the development, localization, and expression of the channel protein.

Unlike HCN2 and HCN4, HCN1 is insensitive to cyclic nucleotides, such as cAMP or cGMP. The reason for this lack of modulation is due to structural differences between the individual channels, further explained in the Structure section.

Filamin A is a cytoplasmic scaffold protein with actin-binding domains whose main function is to link transmembrane proteins to the actin cytoskeleton. Filamin A is known to interact with HCN1 and contributes to localizing the channel to specific neuronal areas and slows down activation and deactivation kinetics. [2324] [457]

Sinus node inhibitors such as cilobradine, ivabradine, and zatebradine are known blockers for HCN channels often used as treatment within the context of heart disease. All three substances block the slow inward current through human HCNs. For HCN1, the blockade happened in a 'closed-channel' state. (16484306) [2305]

Cannabinoids have also shown interaction with HCN1 and are thought to impact long-term potentiation (LTP), and spatial memory formation in the hippocampus [2325].

HCN1-selective compounds have been described [2326]

TRIP8 is brain-specific cytoplasmic protein, of which nine isoform were identified. TRIP8b is known to interact with all HCN, the results of the interactions depending on the type of HCN and TRIP8b isoform involved. TRIP8b (1a–4) and TRIP8b (1a), are major splice variants presen in the hippocampus. They enable a correct localization of HCN1, upregulate HCN1 expression in heterologous systems and promote its dendritic expression. Conversely, TRIP8b (1a) downregulates HCN1 surface expression in X. laevis oocytes and inhibits the abnormal expression of HCN1 in the axons of pyramidal neurons [2293]


For further compounds interactions, please consult the following resource

- History

References

54

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).

323

Notomi T et al. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain.
J. Comp. Neurol., 2004 Apr 5 , 471 (241-76).

324

Lorincz A et al. Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites.
Nat. Neurosci., 2002 Nov , 5 (1185-93).

337

Monteggia LM et al. Cloning and localization of the hyperpolarization-activated cyclic nucleotide-gated channel family in rat brain.
Brain Res. Mol. Brain Res., 2000 Sep 30 , 81 (129-39).

338

Moosmang S et al. Differential distribution of four hyperpolarization-activated cation channels in mouse brain.
Biol. Chem., 1999 Jul-Aug , 380 (975-80).

454

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

455

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

456

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).

457

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

1690

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

1692

Tanimoto N et al. HCN1 channels significantly shape retinal photoresponses.
Adv. Exp. Med. Biol., 2012 , 723 (807-12).

1693

Scicchitano P et al. HCN channels and heart rate.
Molecules, 2012 , 17 (4225-35).

2295

He C et al. Neurophysiology of HCN channels: From cellular functions to multiple regulations.
Prog. Neurobiol., 2014 Jan , 112 (1-23).

2299

Lee CH et al. Structures of the Human HCN1 Hyperpolarization-Activated Channel.
Cell, 2017Jan12, 168 (111-120.e11).

2300

Wainger BJ et al. Molecular mechanism of cAMP modulation of HCN pacemaker channels.
Nature, 2001 Jun 14 , 411 (805-10).

2305

Stieber J et al. Bradycardic and proarrhythmic properties of sinus node inhibitors.
Mol Pharmacol, 2006Apr, 69 (1328-37).

2306

Santoro B et al. Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders.
Annu Rev Pharmacol Toxicol, 2020Jan06, 60 (109-131).

2307

Shah MM Cortical HCN channels: function, trafficking and plasticity.
J. Physiol. (Lond.), 2014 Jul 1 , 592 (2711-9).

2312

Momin A et al. Role of the hyperpolarization-activated current Ih in somatosensory neurons.
J. Physiol. (Lond.), 2008 Dec 15 , 586 (5911-29).

2317

Chaplan SR et al. Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain.
J. Neurosci., 2003 Feb 15 , 23 (1169-78).

2318

Lainez S et al. HCN3 ion channels: roles in sensory neuronal excitability and pain.
J Physiol, 2019Sep, 597 (4661-4675).

2321

Nava C et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy.
Nat. Genet., 2014 Jun , 46 (640-5).

2324

Gravante B et al. Interaction of the pacemaker channel HCN1 with filamin A.
J. Biol. Chem., 2004 Oct 15 , 279 (43847-53).

2325

Maroso M et al. Cannabinoid Control of Learning and Memory through HCN Channels.
Neuron, 2016Mar02, 89 (1059-73).

2326

McClure KJ et al. Discovery of a novel series of selective HCN1 blockers.
Bioorg. Med. Chem. Lett., 2011 Sep 15 , 21 (5197-201).

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Credits

Contributors: Katherine Johnston, Rajnish Ranjan, Michael Schartner, Nitin Khanna

To cite this page: [Contributors] Channelpedia https://channelpedia.epfl.ch/wikipages/61/ , accessed on 2024 Dec 21