HCN2

Target not currently curated in GtoImmuPdb

Target id: 401

Nomenclature: HCN2

Family: Cyclic nucleotide-regulated channels (CNG)

Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Voltage Dependence
Rank order lists
Activators
Channel Blockers
Immuno Process Associations
Tissue Distribution
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
References
Contributors
How to cite this page

Gene and Protein Information
Species	TM	P Loops	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	6	1	889	19p13.3	HCN2	hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2	35
Mouse	6	1	863	10 C1	Hcn2	hyperpolarization-activated, cyclic nucleotide-gated K+ 2	34,51
Rat	6	1	863	7q11	Hcn2	hyperpolarization activated cyclic nucleotide gated potassium and sodium channel 2	40

Previous and Unofficial Names
BCNG2 \| HAC1 \| hyperpolarization activated cyclic nucleotide gated potassium channel 2 \| hyperpolarization-activated, cyclic nucleotide-gated K+ 2 \| hyperpolarization-activated

Previous and Unofficial Names

BCNG2 | HAC1 | hyperpolarization activated cyclic nucleotide gated potassium channel 2 | hyperpolarization-activated, cyclic nucleotide-gated K+ 2 | hyperpolarization-activated

Database Links
Alphafold	Q9UL51 (Hs), O88703 (Mm), Q9JKA9 (Rn)
CATH/Gene3D	2.60.120.10
ChEMBL Target	CHEMBL1795172 (Hs), CHEMBL1250408 (Mm)
Ensembl Gene	ENSG00000099822 (Hs), ENSMUSG00000020331 (Mm), ENSRNOG00000008831 (Rn)
Entrez Gene	610 (Hs), 15166 (Mm), 114244 (Rn)
Human Protein Atlas	ENSG00000099822 (Hs)
KEGG Gene	hsa:610 (Hs), mmu:15166 (Mm), rno:114244 (Rn)
OMIM	602781 (Hs)
Pharos	Q9UL51 (Hs)
RefSeq Nucleotide	NM_001194 (Hs), NM_008226 (Mm), NM_053684 (Rn)
RefSeq Protein	NP_001185 (Hs), NP_032252 (Mm), NP_446136 (Rn)
SynPHARM	5504 (in complex with cyclic AMP) 5505 (in complex with cyclic GMP)
UniProtKB	Q9UL51 (Hs), O88703 (Mm), Q9JKA9 (Rn)
Wikipedia	HCN2 (Hs)

Associated Proteins

Heteromeric Pore-forming Subunits
Name	References
HCN1	43,58
HCN4	43

Auxiliary Subunits
Name	References
KCNE2	2,48,65
Trip8b	1,5,30

Other Associated Proteins
Name	References
KCR1	39
Tamalin, S-SCAM and Mint2	27
C-terminal Src kinase	68
K_2P9.1	37
Protein kinase G (PKG) 2	20

Ion Selectivity and Conductance

Species:	None
Rank order:	K⁺ > Na⁺ > Ca²⁺ [1.5 - 35.0 pS]
References:	10,33,38,66

Voltage Dependence

	V_0.5 (mV)	τ (msec)	Reference	Cell type	Species
Activation	-130.0 – -136.0 (median: -132.0)	-	9,60	Xenopus laevis oocyte	Mouse
Inactivation	-	-		Xenopus laevis oocyte	Mouse
Comments	Inside-out patch.

	V_0.5 (mV)	τ (msec)	Reference	Cell type	Species
Activation	-95.0 – -103.0 (median: -100.0)	200.0 – 500.0	26,33,54	HEK 293 cells.	Human
Inactivation	-	-		HEK 293 cells.	Human
Comments	V_0.5 and τ-values are strongly influenced by experimental parameters such as temperature, pH and pulse protocol.

	V_0.5 (mV)	τ (msec)	Reference	Cell type	Species
Activation	-78.0	-	9	Xenopus laevis oocyte	Mouse
Inactivation	-	-		Xenopus laevis oocyte	Mouse
Comments	Whole-cell patch clamp.

Activators (Human)
cyclic AMP > cyclic GMP

Activators (Human)

cyclic AMP > cyclic GMP

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Activators

Key to terms and symbols

View all chemical structures

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Ligand		Sp.	Action	Value	Parameter	Concentration range (M)	Holding voltage (mV)	Reference
cyclic AMP		Mm	Agonist	6.3	pK_i	-	-40.0	34
⤷	pK_i 6.3 [34] Holding voltage: -40.0 mV
cyclic GMP		Mm	Agonist	5.2	pK_i	-	-40.0	34
⤷	pK_i 5.2 [34] Holding voltage: -40.0 mV
PIP₂		Mm	-	5.0	pEC₅₀	-	-35.0	47
⤷	pEC₅₀ 5.0 (EC₅₀ 1.09x10^-5 M) [47] Holding voltage: -35.0 mV
cyclic CMP		Mm	-	4.5	pEC₅₀	-	-40.0	69
⤷	pEC₅₀ 4.5 (EC₅₀ 3x10^-5 M) [69] Holding voltage: -40.0 mV

Activator Comments

cAMP and cGMP shift V_0.5 by +10 to +20 mV [34-35,50,60].

Channel Blockers

Key to terms and symbols

View all chemical structures

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Ligand		Sp.	Action	Value	Parameter	Concentration range (M)	Holding voltage (mV)	Reference
MEL57A		Mm	-	4.9	pEC₅₀	-	-	11
⤷	pEC₅₀ 4.9 (EC₅₀ 1.256x10^-5 M) [11]
EC18		Mm	-	4.7	pEC₅₀	-	-	11
⤷	pEC₅₀ 4.7 (EC₅₀ 1.935x10^-5 M) [11]
zatebradine		Hs	Antagonist	5.7	pIC₅₀	-	-40.0	55
⤷	pIC₅₀ 5.7 [55] Holding voltage: -40.0 mV
ivabradine		Mm	Antagonist	5.6	pIC₅₀	-	-	55
⤷	pIC₅₀ 5.6 (IC₅₀ 2.29x10^-6 M) [55]
cilobradine		Hs	Antagonist	5.1	pIC₅₀	-	-40.0	55
⤷	pIC₅₀ 5.1 [55] Holding voltage: -40.0 mV
clonidine		Mm	Antagonist	5.1	pIC₅₀	-	-40.0	28
⤷	pIC₅₀ 5.1 (IC₅₀ 8.09x10^-6 M) [28] Holding voltage: -40.0 mV
ZD7288		Hs	Antagonist	4.4	pIC₅₀	-	-	54
⤷	pIC₅₀ 4.4 (IC₅₀ 4.1x10^-5 M) [54]
Cs⁺		Hs	Antagonist	3.7	pIC₅₀	-	-40.0	54
⤷	pIC₅₀ 3.7 (IC₅₀ 2.06x10^-7 M) [54] Holding voltage: -40.0 mV
Mg²⁺		Mm	-	3.2	pIC₅₀	-	50.0	59
⤷	pIC₅₀ 3.2 [59] Holding voltage: 50.0 mV

View species-specific channel blocker tables

Channel Blocker Comments

Propofol inhibits and slows activation of the mouse HCN2 channel at clinically relevant concentrations [4].

Immuno Process Associations

Immuno Process:

Inflammation

Tissue Distribution

Brain.

Species:	Human
Technique:	Northern Blot
References:	35

Heart.

Species:	Human
Technique:	Northern Blot
References:	35

Cochlear and vestibular hair cells.

Species:	Mouse
Technique:	Immunohistochemistry and patch clamp electrophysiology.
References:	23-24,49

Brain.

Species:	Mouse
Technique:	In situ hybridisation
References:	41

Heart.

Species:	Mouse
Technique:	In situ hybridisation, RT-PCR and immunohistochemistry.
References:	22,42

Gastrointestinal (GI) tract

Species:	Mouse
Technique:	Immunohistochemistry
References:	63

Pancreatic beta cells.

Species:	Mouse
Technique:	Voltage-clamp.
References:	16,67

Auditory brainstem and midbrain (ventral cochlear nucleus, principle neurons of the lateral and medial super olive, neurons of the ventral nucleus of the lateral lemniscus).

Species:	Rat
Technique:	Immunohistochemistry
References:	29

Urinary bladder.

Species:	Rat
Technique:	RT-PCR and Western blot.
References:	21

Heart.

Species:	Rat
Technique:	RNAse protection assay.
References:	53

Brain.

Species:	Rat
Technique:	Immunohistochemistry
References:	45

Pancreatic beta cells.

Species:	Rat
Technique:	Voltage-clamp.
References:	16,67

Retina (bipolar cell bodies, type 5 bipolar cells).

Species:	Rat
Technique:	Immunohistochemistry
References:	44

Physiological Functions

Modulation of firing mode of thalamic neurons.

Species:	Mouse
Tissue:	Brain.
References:	32

Determination of resting membrane potential.

Species:	Mouse
Tissue:	Neurones, cardiac pacemaker cells.
References:	32

Involvement in retinal photoresponses to dim light.

Species:	Mouse
Tissue:	Retina
References:	12

Ammonium transport in the distal nephron.

Species:	Rat
Tissue:	Kidney
References:	6

Involvement in inflammatory and neuropathic pain.

Species:	Mouse
Tissue:	Brain and peripheral nervous system.
References:	15,17-18,46,61

Modulation of synaptic plasticity in the hippocampal direct perforant path.

Species:	Mouse
Tissue:	Brain
References:	36

Modulation of L-type calcium channel inactivation.

Species:	Rat
Tissue:	Heart
References:	31

Constraint of excitatory synaptic integration in reticular thalamic nucleus (RTN) neurons.

Species:	Mouse
Tissue:	Brain
References:	64

Physiological Consequences of Altering Gene Expression

The HCN2 knockout mouse has absence epilepsy, ataxia and sinus dysrhythmia.

Species:	Mouse
Tissue:	Brain and heart.
Technique:	Knockout
References:	32

Phenotypes, Alleles and Disease Models

Mouse data from MGI

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Allele	Composition & genetic background	Accession	Phenotype Id	Phenotype	Reference
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0003412	abnormal afterhyperpolarization	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0002572	abnormal emotion/affect behavior	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001406	abnormal gait	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0003312	abnormal locomotor coordination	PMID: 19150498
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0002272	abnormal nervous system electrophysiology	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001504	abnormal posture	PMID: 19150498
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0006142	abnormal sinoatrial node conduction	PMID: 12514127
Hcn2^tm1Ldw\|Hcn2^tm2Ldw\|Myl7⁺\|Myl7^tm1(cre)Krc	Hcn2^tm1Ldw/Hcn2^tm2Ldw,Myl7^tm1(cre)Krc/Myl7⁺ involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:107495 MGI:1298210	MP:0006142	abnormal sinoatrial node conduction	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0008840	abnormal spike wave discharge	PMID: 19150498
Hcn2⁺\|Hcn2^ap	Hcn2^ap/Hcn2⁺ DW/Pas-Hcn2	MGI:1298210	MP:0008840	abnormal spike wave discharge	PMID: 19150498
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0003470	abnormal summary potential	PMID: 12514127
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0003216	absence seizures	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0003216	absence seizures	PMID: 19150498
Hcn2⁺\|Hcn2^ap	Hcn2^ap/Hcn2⁺ DW/Pas-Hcn2	MGI:1298210	MP:0003216	absence seizures	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001393	ataxia	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001258	decreased body length	PMID: 19150498
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0001262	decreased body weight	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001262	decreased body weight	PMID: 19150498
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0003488	decreased channel response intensity	PMID: 12514127
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0001402	hypoactivity	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001402	hypoactivity	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001525	impaired balance	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001522	impaired swimming	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0001409	increased stereotypic behavior	PMID: 19150498
Hcn2⁺\|Hcn2^ap	Hcn2^ap/Hcn2⁺ DW/Pas-Hcn2	MGI:1298210	MP:0002906	increased susceptibility to pharmacologically induced seizures	PMID: 19150498
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0001636	irregular heartbeat	PMID: 12514127
Hcn2^tm1Ldw\|Hcn2^tm2Ldw\|Myl7⁺\|Myl7^tm1(cre)Krc	Hcn2^tm1Ldw/Hcn2^tm2Ldw,Myl7^tm1(cre)Krc/Myl7⁺ involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:107495 MGI:1298210	MP:0001636	irregular heartbeat	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0002083	premature death	PMID: 19150498
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0003997	tonic-clonic seizures	PMID: 19150498
Hcn2^tm1Ldw	Hcn2^tm1Ldw/Hcn2^tm1Ldw involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:1298210	MP:0000745	tremors	PMID: 12514127
Hcn2^ap	Hcn2^ap/Hcn2^ap DW/Pas-Hcn2	MGI:1298210	MP:0000745	tremors	PMID: 19150498

Clinically-Relevant Mutations and Pathophysiology

Disease:

Febrile seizures, familial, 1; FEB1

OMIM:

121210

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Type	Species	Amino acid change	Nucleotide change	Description	Reference
In-frame deletion	Human	P719_P721del	c.2156-2164delCGCCGCCGC	The triple proline deletion (delPPP) in HCN2 is associated with febrile seizure.	13

Disease:

Generalized epilepsy with febrile seizures plus, type 1; GEFSP1

Synonyms:	Generalized epilepsy with febrile seizures-plus [Disease Ontology: DOID:0060170] [Orphanet: ORPHA36387]
Disease Ontology:	DOID:0060170
OMIM:	604233
Orphanet:	ORPHA36387

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Type	Species	Amino acid change	Nucleotide change	Description	Reference
Missense	Human	E515K		In patients with IGE the mutation E515K in HCN2 causes elevated neuronal activity.	14
Missense	Human	R527Q		In patients with IGE the mutation R527Q results in decreased slope of the conductance-voltage relation.	56

Disease:

Sudden unexpected death in epilepsy

Synonyms:

SUDEP

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Type	Species	Amino acid change	Nucleotide change	Description	Reference
Missense	Human	F738C		The F738C variant in HCN2 affects the highly conserved residues in the carboxyl-cytoplasmic tail region.	57
Missense	Human	P802S		The P802S variant in HCN2 affects the highly conserved residues in the carboxyl-cytoplasmic tail region.	57

Gene Expression and Pathophysiology

Upregulation of HCN2 mRNA levels in hypertrophied myocytes from rat left ventricle.

Tissue or cell type:	Cardiac myocytes.
Pathophysiology:	Cardiac hypertrophy.
Species:	Rat
Technique:
References:	19

Expression in cardiac ventricles of hypertrophied aged rats.

Tissue or cell type:	Ventricle.
Pathophysiology:	Induction of arrhythmia in heart failure.
Species:	Rat
Technique:
References:	7

Downregulation of HCN2 in globus pallidus in mouse model of Parkinson’s disease.

Tissue or cell type:	Globus pallidus.
Pathophysiology:	Parkinson’s disease.
Species:	Mouse
Technique:
References:	8

Increase in HCN2 expression in the thalamocortical neurons of epileptic rats (WAG/Rij).

Tissue or cell type:	Thalamocortical neuons.
Pathophysiology:	Absence epilepsy.
Species:	Rat
Technique:
References:	3,25

Elevated HCN2 expression in SP-mediated spinal pain processing.

Tissue or cell type:	Spinal dorsal horn.
Pathophysiology:	Inflammatory pain.
Species:	Rat
Technique:	Unilateral injection of complete Freund's adjuvant (CFA).
References:	46

Increased HCN2 expression in the mesocorticolimbic system via cocaine sensitization.

Tissue or cell type:	Ventral tegmental area, prefrontal cortex, nucleus accumbens, and hippocampus.
Pathophysiology:	Drug abuse.
Species:	Rat
Technique:	Western blot.
References:	52

Increased HCN2 expression in ventricular cells in heart after acute myocardial infarction (AMI).

Tissue or cell type:	Ventricle.
Pathophysiology:
Species:	Rat
Technique:	RT-PCR, immunohistochemistry and Western blot.
References:	62

References

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1. Bankston JR, Camp SS, DiMaio F, Lewis AS, Chetkovich DM, Zagotta WN. (2012) Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels. Proc Natl Acad Sci USA, 109 (20): 7899-904. [PMID:22550182]

2. Brandt MC, Endres-Becker J, Zagidullin N, Motloch LJ, Er F, Rottlaender D, Michels G, Herzig S, Hoppe UC. (2009) Effects of KCNE2 on HCN isoforms: distinct modulation of membrane expression and single channel properties. Am J Physiol Heart Circ Physiol, 297 (1): H355-63. [PMID:19429827]

3. Budde T, Caputi L, Kanyshkova T, Staak R, Abrahamczik C, Munsch T, Pape HC. (2005) Impaired regulation of thalamic pacemaker channels through an imbalance of subunit expression in absence epilepsy. J Neurosci, 25 (43): 9871-82. [PMID:16251434]

4. Cacheaux LP, Topf N, Tibbs GR, Schaefer UR, Levi R, Harrison NL, Abbott GW, Goldstein PA. (2005) Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol. J Pharmacol Exp Ther, 315 (2): 517-25. [PMID:16033909]

5. Cao-Ehlker X, Zong X, Hammelmann V, Gruner C, Fenske S, Michalakis S, Wahl-Schott C, Biel M. (2013) Up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by specific interaction with K+ channel tetramerization domain-containing protein 3 (KCTD3). J Biol Chem, 288 (11): 7580-9. [PMID:23382386]

6. Carrisoza-Gaytán R, Rangel C, Salvador C, Saldaña-Meyer R, Escalona C, Satlin LM, Liu W, Zavilowitz B, Trujillo J, Bobadilla NA et al.. (2011) The hyperpolarization-activated cyclic nucleotide-gated HCN2 channel transports ammonium in the distal nephron. Kidney Int, 80 (8): 832-40. [PMID:21796099]

7. Cerbai E, Mugelli A. (2006) I(f) in non-pacemaker cells: role and pharmacological implications. Pharmacol Res, 53 (5): 416-23. [PMID:16713285]

8. Chan CS, Glajch KE, Gertler TS, Guzman JN, Mercer JN, Lewis AS, Goldberg AB, Tkatch T, Shigemoto R, Fleming SM et al.. (2011) HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease. Nat Neurosci, 14 (1): 85-92. [PMID:21076425]

9. Chen S, Wang J, Siegelbaum SA. (2001) Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J Gen Physiol, 117 (5): 491-504. [PMID:11331358]

10. Dekker JP, Yellen G. (2006) Cooperative gating between single HCN pacemaker channels. J Gen Physiol, 128 (5): 561-7. [PMID:17043149]

11. Del Lungo M, Melchiorre M, Guandalini L, Sartiani L, Mugelli A, Koncz I, Szel T, Varro A, Romanelli MN, Cerbai E. (2012) Novel blockers of hyperpolarization-activated current with isoform selectivity in recombinant cells and native tissue. Br J Pharmacol, 166 (2): 602-16. [PMID:22091830]

12. Della Santina L, Piano I, Cangiano L, Caputo A, Ludwig A, Cervetto L, Gargini C. (2012) Processing of retinal signals in normal and HCN deficient mice. PLoS ONE, 7 (1): e29812. [PMID:22279546]

13. Dibbens LM, Reid CA, Hodgson B, Thomas EA, Phillips AM, Gazina E, Cromer BA, Clarke AL, Baram TZ, Scheffer IE et al.. (2010) Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann Neurol, 67 (4): 542-6. [PMID:20437590]

14. DiFrancesco JC, Barbuti A, Milanesi R, Coco S, Bucchi A, Bottelli G, Ferrarese C, Franceschetti S, Terragni B, Baruscotti M et al.. (2011) Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy. J Neurosci, 31 (48): 17327-37. [PMID:22131395]

15. Du L, Wang SJ, Cui J, He WJ, Ruan HZ. (2013) Inhibition of HCN channels within the periaqueductal gray attenuates neuropathic pain in rats. Behav Neurosci, 127 (2): 325-9. [PMID:23398435]

16. El-Kholy W, MacDonald PE, Fox JM, Bhattacharjee A, Xue T, Gao X, Zhang Y, Stieber J, Li RA, Tsushima RG et al.. (2007) Hyperpolarization-activated cyclic nucleotide-gated channels in pancreatic beta-cells. Mol Endocrinol, 21 (3): 753-64. [PMID:17158221]

17. Emery EC, Young GT, Berrocoso EM, Chen L, McNaughton PA. (2011) HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science, 333 (6048): 1462-6. [PMID:21903816]

18. Emery EC, Young GT, McNaughton PA. (2012) HCN2 ion channels: an emerging role as the pacemakers of pain. Trends Pharmacol Sci, 33 (8): 456-63. [PMID:22613784]

19. Fernández-Velasco M, Goren N, Benito G, Blanco-Rivero J, Boscá L, Delgado C. (2003) Regional distribution of hyperpolarization-activated current (If) and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts. J Physiol (Lond.), 553 (Pt 2): 395-405. [PMID:14514868]

20. Hammelmann V, Zong X, Hofmann F, Michalakis S, Biel M. (2011) The cGMP-dependent protein kinase II Is an inhibitory modulator of the hyperpolarization-activated HCN2 channel. PLoS ONE, 6 (2): e17078. [PMID:21347269]

21. He P, Deng J, Zhong X, Zhou Z, Song B, Li L. (2012) Identification of a hyperpolarization-activated cyclic nucleotide-gated channel and its subtypes in the urinary bladder of the rat. Urology, 79 (6): 1411.e7-13. [PMID:22446339]

22. Herrmann S, Layh B, Ludwig A. (2011) Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart. J Mol Cell Cardiol, 51 (6): 997-1006. [PMID:21945247]

23. Horwitz GC, Lelli A, Géléoc GS, Holt JR. (2010) HCN channels are not required for mechanotransduction in sensory hair cells of the mouse inner ear. PLoS ONE, 5 (1): e8627. [PMID:20062532]

24. Horwitz GC, Risner-Janiczek JR, Jones SM, Holt JR. (2011) HCN channels expressed in the inner ear are necessary for normal balance function. J Neurosci, 31 (46): 16814-25. [PMID:22090507]

25. Kanyshkova T, Meuth P, Bista P, Liu Z, Ehling P, Caputi L, Doengi M, Chetkovich DM, Pape HC, Budde T. (2012) Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains. Neurobiol Dis, 45 (1): 450-61. [PMID:21945537]

26. Kaupp UB, Seifert R. (2001) Molecular diversity of pacemaker ion channels. Annu Rev Physiol, 63: 235-57. [PMID:11181956]

27. Kimura K, Kitano J, Nakajima Y, Nakanishi S. (2004) Hyperpolarization-activated, cyclic nucleotide-gated HCN2 cation channel forms a protein assembly with multiple neuronal scaffold proteins in distinct modes of protein-protein interaction. Genes Cells, 9 (7): 631-40. [PMID:15265006]

28. Knaus A, Zong X, Beetz N, Jahns R, Lohse MJ, Biel M, Hein L. (2007) Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine. Circulation, 115 (7): 872-80. [PMID:17261653]

29. Koch U, Braun M, Kapfer C, Grothe B. (2004) Distribution of HCN1 and HCN2 in rat auditory brainstem nuclei. Eur J Neurosci, 20 (1): 79-91. [PMID:15245481]

30. Lewis AS, Vaidya SP, Blaiss CA, Liu Z, Stoub TR, Brager DH, Chen X, Bender RA, Estep CM, Popov AB et al.. (2011) Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J Neurosci, 31 (20): 7424-40. [PMID:21593326]

31. Lin YC, Huang J, Zhang Q, Hollander JM, Frisbee JC, Martin KH, Nestor C, Goodman R, Yu HG. (2010) Inactivation of L-type calcium channel modulated by HCN2 channel. Am J Physiol, Cell Physiol, 298 (5): C1029-37. [PMID:20164379]

32. Ludwig A, Budde T, Stieber J, Moosmang S, Wahl C, Holthoff K, Langebartels A, Wotjak C, Munsch T, Zong X, Feil S, Feil R, Lancel M, Chien KR, Konnerth A, Pape HC, Biel M, Hofmann F. (2003) Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J, 22 (2): 216-24. [PMID:12514127]

33. Ludwig A, Zong X, Hofmann F, Biel M. (1999) Structure and function of cardiac pacemaker channels. Cell Physiol Biochem, 9 (4-5): 179-86. [PMID:10575196]

34. Ludwig A, Zong X, Jeglitsch M, Hofmann F, Biel M. (1998) A family of hyperpolarization-activated mammalian cation channels. Nature, 393 (6685): 587-91. [PMID:9634236]

35. Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M. (1999) Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J, 18 (9): 2323-9. [PMID:10228147]

36. Matt L, Michalakis S, Hofmann F, Hammelmann V, Ludwig A, Biel M, Kleppisch T. (2011) HCN2 channels in local inhibitory interneurons constrain LTP in the hippocampal direct perforant path. Cell Mol Life Sci, 68 (1): 125-37. [PMID:20623157]

37. Meuth SG, Kanyshkova T, Meuth P, Landgraf P, Munsch T, Ludwig A, Hofmann F, Pape HC, Budde T. (2006) Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. J Neurophysiol, 96 (3): 1517-29. [PMID:16760342]

38. Michels G, Er F, Khan I, Südkamp M, Herzig S, Hoppe UC. (2005) Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation, 111 (4): 399-404. [PMID:15687126]

39. Michels G, Er F, Khan IF, Endres-Becker J, Brandt MC, Gassanov N, Johns DC, Hoppe UC. (2008) K+ channel regulator KCR1 suppresses heart rhythm by modulating the pacemaker current If. PLoS ONE, 3 (1): e1511. [PMID:18231597]

40. Monteggia LM, Eisch AJ, Tang MD, Kaczmarek LK, Nestler EJ. (2000) Cloning and localization of the hyperpolarization-activated cyclic nucleotide-gated channel family in rat brain. Brain Res Mol Brain Res, 81 (1-2): 129-39. [PMID:11000485]

41. Moosmang S, Biel M, Hofmann F, Ludwig A. (1999) Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol Chem, 380 (7-8): 975-80. [PMID:10494850]

42. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A. (2001) Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem, 268 (6): 1646-52. [PMID:11248683]

43. Much B, Wahl-Schott C, Zong X, Schneider A, Baumann L, Moosmang S, Ludwig A, Biel M. (2003) Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels. J Biol Chem, 278 (44): 43781-6. [PMID:12928435]

44. Müller F, Scholten A, Ivanova E, Haverkamp S, Kremmer E, Kaupp UB. (2003) HCN channels are expressed differentially in retinal bipolar cells and concentrated at synaptic terminals. Eur J Neurosci, 17 (10): 2084-96. [PMID:12786975]

45. Notomi T, Shigemoto R. (2004) Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol, 471 (3): 241-76. [PMID:14991560]

46. Papp I, Holló K, Antal M. (2010) Plasticity of hyperpolarization-activated and cyclic nucleotid-gated cation channel subunit 2 expression in the spinal dorsal horn in inflammatory pain. Eur J Neurosci, 32 (7): 1193-201. [PMID:20726890]

47. Pian P, Bucchi A, Robinson RB, Siegelbaum SA. (2006) Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2. J Gen Physiol, 128 (5): 593-604. [PMID:17074978]

48. Qu J, Kryukova Y, Potapova IA, Doronin SV, Larsen M, Krishnamurthy G, Cohen IS, Robinson RB. (2004) MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. J Biol Chem, 279 (42): 43497-502. [PMID:15292247]

49. Ramakrishnan NA, Drescher MJ, Khan KM, Hatfield JS, Drescher DG. (2012) HCN1 and HCN2 proteins are expressed in cochlear hair cells: HCN1 can form a ternary complex with protocadherin 15 CD3 and F-actin-binding filamin A or can interact with HCN2. J Biol Chem, 287 (45): 37628-46. [PMID:22948144]

50. Robinson RB, Siegelbaum SA. (2003) Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol, 65: 453-80. [PMID:12471170]

51. Santoro B, Grant SG, Bartsch D, Kandel ER. (1997) Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proc Natl Acad Sci USA, 94 (26): 14815-20. [PMID:9405696]

52. Santos-Vera B, Vázquez-Torres R, Marrero HG, Acevedo JM, Arencibia-Albite F, Vélez-Hernández ME, Miranda JD, Jiménez-Rivera CA. (2013) Cocaine sensitization increases I h current channel subunit 2 (HCN₂) protein expression in structures of the mesocorticolimbic system. J Mol Neurosci, 50 (1): 234-45. [PMID:23203153]

53. Shi W, Wymore R, Yu H, Wu J, Wymore RT, Pan Z, Robinson RB, Dixon JE, McKinnon D, Cohen IS. (1999) Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res, 85 (1): e1-6. [PMID:10400919]

54. Stieber J, Stöckl G, Herrmann S, Hassfurth B, Hofmann F. (2005) Functional expression of the human HCN3 channel. J Biol Chem, 280 (41): 34635-43. [PMID:16043489]

55. Stieber J, Wieland K, Stöckl G, Ludwig A, Hofmann F. (2006) Bradycardic and proarrhythmic properties of sinus node inhibitors. Mol Pharmacol, 69 (4): 1328-37. [PMID:16387796]

56. Tang B, Sander T, Craven KB, Hempelmann A, Escayg A. (2008) Mutation analysis of the hyperpolarization-activated cyclic nucleotide-gated channels HCN1 and HCN2 in idiopathic generalized epilepsy. Neurobiol Dis, 29 (1): 59-70. [PMID:17931874]

57. Tu E, Waterhouse L, Duflou J, Bagnall RD, Semsarian C. (2011) Genetic analysis of hyperpolarization-activated cyclic nucleotide-gated cation channels in sudden unexpected death in epilepsy cases. Brain Pathol, 21 (6): 692-8. [PMID:21615589]

58. Ulens C, Tytgat J. (2001) Functional heteromerization of HCN1 and HCN2 pacemaker channels. J Biol Chem, 276 (9): 6069-72. [PMID:11133998]

59. Vemana S, Pandey S, Larsson HP. (2008) Intracellular Mg2+ is a voltage-dependent pore blocker of HCN channels. Am J Physiol, Cell Physiol, 295 (2): C557-65. [PMID:18579800]

60. Wainger BJ, DeGennaro M, Santoro B, Siegelbaum SA, Tibbs GR. (2001) Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature, 411 (6839): 805-10. [PMID:11459060]

61. Wan Y. (2008) Involvement of hyperpolarization-activated, cyclic nucleotide-gated cation channels in dorsal root ganglion in neuropathic pain. Sheng Li Xue Bao, 60 (5): 579-80. [PMID:18958363]

62. Xia S, Wang Y, Zhang Y, Deng SB, Du JL, Wang XC, She Q. (2010) Dynamic changes in HCN2, HCN4, KCNE1, and KCNE2 expression in ventricular cells from acute myocardial infarction rat hearts. Biochem Biophys Res Commun, 395 (3): 330-5. [PMID:20381460]

63. Yang S, Xiong CJ, Sun HM, Li XS, Zhang GQ, Wu B, Zhou DS. (2012) The distribution of HCN2-positive cells in the gastrointestinal tract of mice. J Anat, 221 (4): 303-10. [PMID:22803609]

64. Ying SW, Jia F, Abbas SY, Hofmann F, Ludwig A, Goldstein PA. (2007) Dendritic HCN2 channels constrain glutamate-driven excitability in reticular thalamic neurons. J Neurosci, 27 (32): 8719-32. [PMID:17687049]

65. Ying SW, Kanda VA, Hu Z, Purtell K, King EC, Abbott GW, Goldstein PA. (2012) Targeted deletion of Kcne2 impairs HCN channel function in mouse thalamocortical circuits. PLoS ONE, 7 (8): e42756. [PMID:22880098]

66. Yu X, Chen XW, Zhou P, Yao L, Liu T, Zhang B, Li Y, Zheng H, Zheng LH, Zhang CX et al.. (2007) Calcium influx through If channels in rat ventricular myocytes. Am J Physiol, Cell Physiol, 292 (3): C1147-55. [PMID:17065201]

67. Zhang Y, Liu Y, Qu J, Hardy A, Zhang N, Diao J, Strijbos PJ, Tsushima R, Robinson RB, Gaisano HY et al.. (2009) Functional characterization of hyperpolarization-activated cyclic nucleotide-gated channels in rat pancreatic beta cells. J Endocrinol, 203 (1): 45-53. [PMID:19654142]

68. Zong X, Eckert C, Yuan H, Wahl-Schott C, Abicht H, Fang L, Li R, Mistrik P, Gerstner A, Much B et al.. (2005) A novel mechanism of modulation of hyperpolarization-activated cyclic nucleotide-gated channels by Src kinase. J Biol Chem, 280 (40): 34224-32. [PMID:16079136]

69. Zong X, Krause S, Chen CC, Krüger J, Gruner C, Cao-Ehlker X, Fenske S, Wahl-Schott C, Biel M. (2012) Regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by cCMP. J Biol Chem, 287 (32): 26506-12. [PMID:22715094]

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