Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBIB44K)

• DOT Name: 5-hydroxytryptamine receptor 4 (HTR4)
• Synonyms: 5-HT-4; 5-HT4; Serotonin receptor 4
• Gene Name: HTR4
• UniProt ID: 5HT4R_HUMAN
• PDB ID: 5EM9; 7XT8; 7XT9; 7XTA
• Pfam ID: PF00001
• Sequence:
  MDKLDANVSSEEGFGSVEKVVLLTFLSTVILMAILGNLLVMVAVCWDRQLRKIKTNYFIV
  SLAFADLLVSVLVMPFGAIELVQDIWIYGEVFCLVRTSLDVLLTTASIFHLCCISLDRYY
  AICCQPLVYRNKMTPLRIALMLGGCWVIPTFISFLPIMQGWNNIGIIDLIEKRKFNQNSN
  STYCVFMVNKPYAITCSVVAFYIPFLLMVLAYYRIYVTAKEHAHQIQMLQRAGASSESRP
  QSADQHSTHRMRTETKAAKTLCIIMGCFCLCWAPFFVTNIVDPFIDYTVPGQVWTAFLWL
  GYINSGLNPFLYAFLNKSFRRAFLIILCCDDERYRRPSILGQTVPCSTTTINGSTHVLRD
  AVECGGQWESQCHPPATSPLVAAQPSDT
• Function: This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. The activity of this receptor is mediated by G proteins that stimulate adenylate cyclase.
• Tissue Specificity: Isoform 5-HT4(A) is expressed in ileum, brain, and atrium, but not in the ventricle.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Serotonergic sy.pse (hsa04726)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Serotonin receptors (R-HSA-390666)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	5-hydroxytryptamine receptor 4 (HTR4) affects the response to substance of Etoposide.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 5-hydroxytryptamine receptor 4 (HTR4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 5-hydroxytryptamine receptor 4 (HTR4).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of 5-hydroxytryptamine receptor 4 (HTR4).	[2]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of 5-hydroxytryptamine receptor 4 (HTR4).	[3]
Selenium	DM25CGV	Approved	Selenium increases the expression of 5-hydroxytryptamine receptor 4 (HTR4).	[4]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
GR-113808	DMFU9VH	Investigative	GR-113808 affects the binding of 5-hydroxytryptamine receptor 4 (HTR4).	[6]

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] 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.
• [3] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [4] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] 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.
• [6] New arylpiperazine derivatives as antagonists of the human cloned 5-HT(4) receptor isoforms. J Med Chem. 2000 Oct 5;43(20):3761-9. doi: 10.1021/jm0009538.
• [7] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.