Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMO1ZYQ)

• DOT Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3)
• Gene Name: HCN3
• Related Disease:
  Alzheimer disease
  Neuralgia
  Parkinson disease
  Neuroblastoma
• UniProt ID: HCN3_HUMAN
• Pfam ID: PF00027 ; PF00520 ; PF08412
• Sequence:
  MEAEQRPAAGASEGATPGLEAVPPVAPPPATAASGPIPKSGPEPKRRHLGTLLQPTVNKF
  SLRVFGSHKAVEIEQERVKSAGAWIIHPYSDFRFYWDLIMLLLMVGNLIVLPVGITFFKE
  ENSPPWIVFNVLSDTFFLLDLVLNFRTGIVVEEGAEILLAPRAIRTRYLRTWFLVDLISS
  IPVDYIFLVVELEPRLDAEVYKTARALRIVRFTKILSLLRLLRLSRLIRYIHQWEEIFHM
  TYDLASAVVRIFNLIGMMLLLCHWDGCLQFLVPMLQDFPPDCWVSINHMVNHSWGRQYSH
  ALFKAMSHMLCIGYGQQAPVGMPDVWLTMLSMIVGATCYAMFIGHATALIQSLDSSRRQY
  QEKYKQVEQYMSFHKLPADTRQRIHEYYEHRYQGKMFDEESILGELSEPLREEIINFTCR
  GLVAHMPLFAHADPSFVTAVLTKLRFEVFQPGDLVVREGSVGRKMYFIQHGLLSVLARGA
  RDTRLTDGSYFGEICLLTRGRRTASVRADTYCRLYSLSVDHFNAVLEEFPMMRRAFETVA
  MDRLLRIGKKNSILQRKRSEPSPGSSGGIMEQHLVQHDRDMARGVRGRAPSTGAQLSGKP
  VLWEPLVHAPLQAAAVTSNVAIALTHQRGPLPLSPDSPATLLARSAWRSAGSPASPLVPV
  RAGPWASTSRLPAPPARTLHASLSRAGRSQVSLLGPPPGGGGRRLGPRGRPLSASQPSLP
  QRATGDGSPGRKGSGSERLPPSGLLAKPPRTAQPPRPPVPEPATPRGLQLSANM
• Function: Hyperpolarization-activated potassium channel. May also facilitate the permeation of sodium ions.
• Tissue Specificity: Detected in brain.
• KEGG Pathway: GnRH secretion (hsa04929)
• Reactome Pathway: HCN channels (R-HSA-1296061)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
Neuralgia	DISWO58J	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[12]

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 decreases the methylation of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3).	[10]

References

• [1] Network-guided analysis of hippocampal proteome identifies novel proteins that colocalize with A in a mice model of early-stage Alzheimer's disease.Neurobiol Dis. 2019 Dec;132:104603. doi: 10.1016/j.nbd.2019.104603. Epub 2019 Sep 5.
• [2] HCN3 ion channels: roles in sensory neuronal excitability and pain.J Physiol. 2019 Sep;597(17):4661-4675. doi: 10.1113/JP278211. Epub 2019 Jul 27.
• [3] Dopamine depletion induced up-regulation of HCN3 enhances rebound excitability of basal ganglia output neurons.Neurobiol Dis. 2009 Apr;34(1):178-88. doi: 10.1016/j.nbd.2009.01.007.
• [4] MEG3, HCN3 and linc01105 influence the proliferation and apoptosis of neuroblastoma cells via the HIF-1 and p53 pathways.Sci Rep. 2016 Nov 8;6:36268. doi: 10.1038/srep36268.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.