Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR94VKQ)

• DOT Name: Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9)
• Synonyms: Nicotinic acetylcholine receptor subunit alpha-9; NACHR alpha-9
• Gene Name: CHRNA9
• UniProt ID: ACHA9_HUMAN
• PDB ID: 4D01; 4UXU; 4UY2; 6HY7
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MNWSHSCISFCWIYFAASRLRAAETADGKYAQKLFNDLFEDYSNALRPVEDTDKVLNVTL
  QITLSQIKDMDERNQILTAYLWIRQIWHDAYLTWDRDQYDGLDSIRIPSDLVWRPDIVLY
  NKADDESSEPVNTNVVLRYDGLITWDAPAITKSSCVVDVTYFPFDNQQCNLTFGSWTYNG
  NQVDIFNALDSGDLSDFIEDVEWEVHGMPAVKNVISYGCCSEPYPDVTFTLLLKRRSSFY
  IVNLLIPCVLISFLAPLSFYLPAASGEKVSLGVTILLAMTVFQLMVAEIMPASENVPLIG
  KYYIATMALITASTALTIMVMNIHFCGAEARPVPHWARVVILKYMSRVLFVYDVGESCLS
  PHHSRERDHLTKVYSKLPESNLKAARNKDLSRKKDMNKRLKNDLGCQGKNPQEAESYCAQ
  YKVLTRNIEYIAKCLKDHKATNSKGSEWKKVAKVIDRFFMWIFFIMVFVMTILIIARAD
• Function: Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding induces a conformation change that leads to the opening of an ion-conducting channel across the plasma membrane. The channel is permeable to a range of divalent cations including calcium, the influx of which may activate a potassium current which hyperpolarizes the cell membrane. In the ear, this may lead to a reduction in basilar membrane motion, altering the activity of auditory nerve fibers and reducing the range of dynamic hearing. This may protect against acoustic trauma. May also regulate keratinocyte adhesion.
• Tissue Specificity: Expressed in cochlea, keratinocytes, pituitary gland, B-cells and T-cells.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Acetylcholine inhibits contraction of outer hair cells (R-HSA-9667769)
  Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)

Molecular Interaction Atlas (MIA) of This DOT

10 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 Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[6]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neuronal acetylcholine receptor subunit alpha-9 (CHRNA9).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] nAChRs-ERK1/2-Egr-1 signaling participates in the developmental toxicity of nicotine by epigenetically down-regulating placental 11beta-HSD2. Toxicol Appl Pharmacol. 2018 Apr 1;344:1-12.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.