Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGIL2YD)

• DOT Name: Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5)
• Gene Name: CHRNA5
• UniProt ID: ACHA5_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MAARGSGPRALRLLLLVQLVAGRCGLAGAAGGAQRGLSEPSSIAKHEDSLLKDLFQDYER
  WVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKV
  IRVPSDSVWTPDIVLFDNADGRFEGTSTKTVIRYNGTVTWTPPANYKSSCTIDVTFFPFD
  LQNCSMKFGSWTYDGSQVDIILEDQDVDKRDFFDNGEWEIVSATGSKGNRTDSCCWYPYV
  TYSFVIKRLPLFYTLFLIIPCIGLSFLTVLVFYLPSNEGEKICLCTSVLVSLTVFLLVIE
  EIIPSSSKVIPLIGEYLVFTMIFVTLSIMVTVFAINIHHRSSSTHNAMAPLVRKIFLHTL
  PKLLCMRSHVDRYFTQKEETESGSGPKSSRNTLEAALDSIRYITRHIMKENDVREVVEDW
  KFIAQVLDRMFLWTFLFVSIVGSLGLFVPVIYKWANILIPVHIGNANK
• Function: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  Highly calcium permeable nicotinic acetylcholine receptors (R-HSA-629597)
  Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)

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
Nicotine	DMWX5CO	Approved	Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) increases the response to substance of Nicotine.	[17]
Cocaine	DMSOX7I	Approved	Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5) decreases the response to substance of Cocaine.	[17]

16 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-5 (CHRNA5).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[8]
Ethanol	DMDRQZU	Approved	Ethanol affects the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[9]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[15]
MCC950	DM6J2UZ	Investigative	MCC950 decreases the expression of Neuronal acetylcholine receptor subunit alpha-5 (CHRNA5).	[16]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] 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.
• [5] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [6] 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.
• [7] Progesterone modulation of alpha5 nAChR subunits influences anxiety-related behavior during estrus cycle. Genes Brain Behav. 2009 Jun;8(4):398-406. doi: 10.1111/j.1601-183X.2009.00476.x. Epub 2009 Feb 11.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Low ethanol concentration alters CHRNA5 RNA levels during early human development. Reprod Toxicol. 2010 Nov;30(3):489-92. doi: 10.1016/j.reprotox.2010.04.011. Epub 2010 May 11.
• [10] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] 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.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] 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.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] The role of 5-nicotinic acetylcholine receptor/NLRP3 signaling pathway in lung adenocarcinoma cell proliferation and migration. Toxicology. 2022 Mar 15;469:153120. doi: 10.1016/j.tox.2022.153120. Epub 2022 Feb 4.
• [17] A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biol Psychiatry. 2008 Dec 1;64(11):922-9. doi: 10.1016/j.biopsych.2008.04.018. Epub 2008 Jun 2.