Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAIV1AK)

• DOT Name: 5-hydroxytryptamine receptor 3A (HTR3A)
• Synonyms: 5-HT3-A; 5-HT3A; 5-hydroxytryptamine receptor 3; 5-HT-3; 5-HT3R; Serotonin receptor 3A; Serotonin-gated ion channel receptor
• Gene Name: HTR3A
• UniProt ID: 5HT3A_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MLLWVQQALLALLLPTLLAQGEARRSRNTTRPALLRLSDYLLTNYRKGVRPVRDWRKPTT
  VSIDVIVYAILNVDEKNQVLTTYIWYRQYWTDEFLQWNPEDFDNITKLSIPTDSIWVPDI
  LINEFVDVGKSPNIPYVYIRHQGEVQNYKPLQVVTACSLDIYNFPFDVQNCSLTFTSWLH
  TIQDINISLWRLPEKVKSDRSVFMNQGEWELLGVLPYFREFSMESSNYYAEMKFYVVIRR
  RPLFYVVSLLLPSIFLMVMDIVGFYLPPNSGERVSFKITLLLGYSVFLIIVSDTLPATAI
  GTPLIGVYFVVCMALLVISLAETIFIVRLVHKQDLQQPVPAWLRHLVLERIAWLLCLREQ
  STSQRPPATSQATKTDDCSAMGNHCSHMGGPQDFEKSPRDRCSPPPPPREASLAVCGLLQ
  ELSSIRQFLEKRDEIREVARDWLRVGSVLDKLLFHIYLLAVLAYSITLVMLWSIWQYA
• Function: Forms serotonin (5-hydroxytryptamine/5-HT3)-activated cation-selective channel complexes, which when activated cause fast, depolarizing responses in neurons.
• Tissue Specificity: Expressed in cerebral cortex, amygdala, hippocampus, and testis. Detected in monocytes of the spleen and tonsil, in small and large intestine, uterus, prostate, ovary and placenta.
• KEGG Pathway:
  Serotonergic sy.pse (hsa04726)
  Taste transduction (hsa04742)
• Reactome Pathway: Neurotransmitter receptors and postsynaptic signal transmission (R-HSA-112314)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	5-hydroxytryptamine receptor 3A (HTR3A) affects the response to substance of Clozapine.	[13]
Gabapentin	DM6T924	Approved	5-hydroxytryptamine receptor 3A (HTR3A) increases the Sleep disturbances (incl subtypes) ADR of Gabapentin.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 5-hydroxytryptamine receptor 3A (HTR3A).	[1]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of 5-hydroxytryptamine receptor 3A (HTR3A).	[2]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 5-hydroxytryptamine receptor 3A (HTR3A).	[2]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[3]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of 5-hydroxytryptamine receptor 3A (HTR3A).	[4]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of 5-hydroxytryptamine receptor 3A (HTR3A).	[5]
Capsaicin	DMGMF6V	Approved	Capsaicin decreases the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[6]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[3]
Metoclopramide	DMFA5MY	Approved	Metoclopramide decreases the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[7]
Sufentanil	DMU7YEL	Approved	Sufentanil affects the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[8]
Hydromorphone	DMHP21E	Approved	Hydromorphone affects the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[8]
Alfentanil	DMVO0UB	Approved	Alfentanil affects the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 5-hydroxytryptamine receptor 3A (HTR3A).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of 5-hydroxytryptamine receptor 3A (HTR3A).	[11]
geraniol	DMS3CBD	Investigative	geraniol decreases the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[6]
gingerol	DMNXYSM	Investigative	gingerol decreases the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[6]
carvacrol	DMINM2D	Investigative	carvacrol increases the activity of 5-hydroxytryptamine receptor 3A (HTR3A).	[6]

2 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 5-hydroxytryptamine receptor 3A (HTR3A).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 5-hydroxytryptamine receptor 3A (HTR3A).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]GR65630	DMMHSYA	Investigative	[3H]GR65630 affects the binding of 5-hydroxytryptamine receptor 3A (HTR3A).	[7]

References

• [1] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [2] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [3] Inhibitory effect of glucocorticoids on human-cloned 5-hydroxytryptamine3A receptor expressed in xenopus oocytes. Anesthesiology. 2004 Sep;101(3):660-5. doi: 10.1097/00000542-200409000-00014.
• [4] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [5] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [6] Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances. Biochem Biophys Res Commun. 2015 Nov 27;467(4):1090-6. doi: 10.1016/j.bbrc.2015.09.074. Epub 2015 Oct 9.
• [7] Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers. Br J Pharmacol. 2005 Oct;146(4):543-52. doi: 10.1038/sj.bjp.0706351.
• [8] The effects of fentanyl-like opioids and hydromorphone on human 5-HT3A receptors. Anesth Analg. 2008 Jul;107(1):107-12. doi: 10.1213/ane.0b013e31817342c2.
• [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] Assessment of caffeine neurotoxicity using novel biomarkers of neural function in SH-SY5Y cells - Is there a need for environmental concern?. Chem Biol Interact. 2022 Sep 25;365:110082. doi: 10.1016/j.cbi.2022.110082. Epub 2022 Aug 5.
• [12] 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.
• [13] Influence of serotonin 3A and 3B receptor genes on clozapine treatment response in schizophrenia. Pharmacogenet Genomics. 2010 Apr;20(4):274-6. doi: 10.1097/FPC.0b013e328337ce3e.
• [14] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.