Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPH3RRX)

• DOT Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4)
• Gene Name: HCN4
• Related Disease:
  Sick sinus syndrome 2, autosomal dominant
  Brugada syndrome 8
  Familial sick sinus syndrome
  Brugada syndrome 1
  Familial thoracic aortic aneurysm and aortic dissection
• UniProt ID: HCN4_HUMAN
• PDB ID: 2MNG; 3OTF; 3U11; 4HBN; 4KL1; 4NVP; 6GYN; 6GYO
• Pfam ID: PF00027 ; PF00520 ; PF08412
• Sequence:
  MDKLPPSMRKRLYSLPQQVGAKAWIMDEEEDAEEEGAGGRQDPSRRSIRLRPLPSPSPSA
  AAGGTESRSSALGAADSEGPARGAGKSSTNGDCRRFRGSLASLGSRGGGSGGTGSGSSHG
  HLHDSAEERRLIAEGDASPGEDRTPPGLAAEPERPGASAQPAASPPPPQQPPQPASASCE
  QPSVDTAIKVEGGAAAGDQILPEAEVRLGQAGFMQRQFGAMLQPGVNKFSLRMFGSQKAV
  EREQERVKSAGFWIIHPYSDFRFYWDLTMLLLMVGNLIIIPVGITFFKDENTTPWIVFNV
  VSDTFFLIDLVLNFRTGIVVEDNTEIILDPQRIKMKYLKSWFMVDFISSIPVDYIFLIVE
  TRIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDLASAVVRIVN
  LIGMMLLLCHWDGCLQFLVPMLQDFPDDCWVSINNMVNNSWGKQYSYALFKAMSHMLCIG
  YGRQAPVGMSDVWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKYKQVEQYMSF
  HKLPPDTRQRIHDYYEHRYQGKMFDEESILGELSEPLREEIINFNCRKLVASMPLFANAD
  PNFVTSMLTKLRFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKETKLADGSYFGE
  ICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVALDRLDRIGKKNSI
  LLHKVQHDLNSGVFNYQENEIIQQIVQHDREMAHCAHRVQAAASATPTPTPVIWTPLIQA
  PLQAAAATTSVAIALTHHPRLPAAIFRPPPGSGLGNLGAGQTPRHLKRLQSLIPSALGSA
  SPASSPSQVDTPSSSSFHIQQLAGFSAPAGLSPLLPSSSSSPPPGACGSPSAPTPSAGVA
  ATTIAGFGHFHKALGGSLSSSDSPLLTPLQPGARSPQAAQPSPAPPGARGGLGLPEHFLP
  PPPSSRSPSSSPGQLGQPPGELSLGLATGPLSTPETPPRQPEPPSLVAGASGGASPVGFT
  PRGGLSPPGHSPGPPRTFPSAPPRASGSHGSLLLPPASSPPPPQVPQRRGTPPLTPGRLT
  QDLKLISASQPALPQDGAQTLRRASPHSSGESMAAFPLFPRAGGGSGGSGSSGGLGPPGR
  PYGAIPGQHVTLPRKTSSGSLPPPLSLFGARATSSGGPPLTAGPQREPGARPEPVRSKLP
  SNL
• Function: Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli.
• Tissue Specificity: Highly expressed in thalamus, testis and in heart, both in ventricle and atrium. Detected at much lower levels in amygdala, substantia nigra, cerebellum and hippocampus.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Taste transduction (hsa04742)
• Reactome Pathway: HCN channels (R-HSA-1296061)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Sick sinus syndrome 2, autosomal dominant	DIS0UITQ	Strong	Autosomal dominant	[1]
Brugada syndrome 8	DISHLZH1	Moderate	Autosomal dominant	[2]
Familial sick sinus syndrome	DISFVIMO	Supportive	Autosomal dominant	[3]
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[4]
Familial thoracic aortic aneurysm and aortic dissection	DIS069FB	Limited	Autosomal dominant	[4]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[7]
Flecainide	DMSQDLE	Approved	Flecainide decreases the activity of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[13]
aconitine	DMFOZ60	Investigative	aconitine increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4).	[10]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Effects of antiarrhythmic drugs on the hyperpolarization-activated cyclic nucleotide-gated channel current. J Pharmacol Sci. 2009 Jun;110(2):150-9. doi: 10.1254/jphs.08312fp. Epub 2009 Jun 5.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [13] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [14] Notch1-mediated histone demethylation of HCN4 contributes to aconitine-induced ventricular myocardial dysrhythmia. Toxicol Lett. 2020 Jul 1;327:19-31. doi: 10.1016/j.toxlet.2020.03.017. Epub 2020 Mar 28.