Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW28QTH)

• DOT Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2)
• Synonyms: Brain cyclic nucleotide-gated channel 2; BCNG-2
• Gene Name: HCN2
• UniProt ID: HCN2_HUMAN
• PDB ID: 2MPF; 3U10
• Pfam ID: PF00027 ; PF00520 ; PF08412
• Sequence:
  MDARGGGGRPGESPGATPAPGPPPPPPPAPPQQQPPPPPPPAPPPGPGPAPPQHPPRAEA
  LPPEAADEGGPRGRLRSRDSSCGRPGTPGAASTAKGSPNGECGRGEPQCSPAGPEGPARG
  PKVSFSCRGAASGPAPGPGPAEEAGSEEAGPAGEPRGSQASFMQRQFGALLQPGVNKFSL
  RMFGSQKAVEREQERVKSAGAWIIHPYSDFRFYWDFTMLLFMVGNLIIIPVGITFFKDET
  TAPWIVFNVVSDTFFLMDLVLNFRTGIVIEDNTEIILDPEKIKKKYLRTWFVVDFVSSIP
  VDYIFLIVEKGIDSEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHMTYDL
  ASAVMRICNLISMMLLLCHWDGCLQFLVPMLQDFPRNCWVSINGMVNHSWSELYSFALFK
  AMSHMLCIGYGRQAPESMTDIWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQYQEKY
  KQVEQYMSFHKLPADFRQKIHDYYEHRYQGKMFDEDSILGELNGPLREEIVNFNCRKLVA
  SMPLFANADPNFVTAMLTKLKFEVFQPGDYIIREGTIGKKMYFIQHGVVSVLTKGNKEMK
  LSDGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDNFNEVLEEYPMMRRAFETVAIDRL
  DRIGKKNSILLHKVQHDLNSGVFNNQENAIIQEIVKYDREMVQQAELGQRVGLFPPPPPP
  PQVTSAIATLQQAAAMSFCPQVARPLVGPLALGSPRLVRRPPPGPAPAAASPGPPPPASP
  PGAPASPRAPRTSPYGGLPAAPLAGPALPARRLSRASRPLSASQPSLPHGAPGPAASTRP
  ASSSTPRLGPTPAARAAAPSPDRRDSASPGAAGGLDPQDSARSRLSSNL
• Function: Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transport ammonium in the distal nephron. Produces a large instantaneous current. Modulated by intracellular chloride ions and pH; acidic pH shifts the activation to more negative voltages.
• Tissue Specificity: Highly expressed throughout the brain. Detected at low levels in heart.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  GnRH secretion (hsa04929)
• Reactome Pathway: HCN channels (R-HSA-1296061)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[4]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[6]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2).	[8]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology. 2015 Feb 3;328:102-11. doi: 10.1016/j.tox.2014.12.018. Epub 2014 Dec 18.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] 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.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.