Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCZQY1U)

• DOT Name: Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3)
• Gene Name: CHRNA3
• Related Disease:
  Neoplasm
  Advanced cancer
  Alcohol dependence
  Alcohol use disorder
  Alpha-1 antitrypsin deficiency
  Alzheimer disease
  Attention deficit hyperactivity disorder
  Autosomal dominant nocturnal frontal lobe epilepsy
  Carcinoma of esophagus
  Chronic bronchitis
  Cocaine addiction
  Congenital anomaly of kidney and urinary tract
  Dysautonomia
  Esophageal cancer
  Gastric cancer
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung squamous cell carcinoma
  Nasopharyngeal carcinoma
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Obesity
  Peripheral arterial disease
  Pulmonary emphysema
  Stomach cancer
  Ulcerative colitis
  High blood pressure
  Lung neoplasm
  Schizophrenia
  Squamous cell carcinoma
  Coronary heart disease
  Nicotine dependence
  Neuroblastoma
• UniProt ID: ACHA3_HUMAN
• PDB ID: 4ZK4; 5SYO; 5TVC; 6PV7; 6PV8
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MGSGPLSLPLALSPPRLLLLLLLSLLPVARASEAEHRLFERLFEDYNEIIRPVANVSDPV
  IIHFEVSMSQLVKVDEVNQIMETNLWLKQIWNDYKLKWNPSDYGGAEFMRVPAQKIWKPD
  IVLYNNAVGDFQVDDKTKALLKYTGEVTWIPPAIFKSSCKIDVTYFPFDYQNCTMKFGSW
  SYDKAKIDLVLIGSSMNLKDYWESGEWAIIKAPGYKHDIKYNCCEEIYPDITYSLYIRRL
  PLFYTINLIIPCLLISFLTVLVFYLPSDCGEKVTLCISVLLSLTVFLLVITETIPSTSLV
  IPLIGEYLLFTMIFVTLSIVITVFVLNVHYRTPTTHTMPSWVKTVFLNLLPRVMFMTRPT
  SNEGNAQKPRPLYGAELSNLNCFSRAESKGCKEGYPCQDGMCGYCHHRRIKISNFSANLT
  RSSSSESVDAVLSLSALSPEIKEAIQSVKYIAENMKAQNEAKEIQDDWKYVAMVIDRIFL
  WVFTLVCILGTAGLFLQPLMAREDA
• 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)
  Cholinergic sy.pse (hsa04725)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)
  Highly calcium permeable nicotinic acetylcholine receptors (R-HSA-629597)
  Highly sodium permeable postsynaptic acetylcholine nicotinic receptors (R-HSA-629587)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[3]
Alcohol use disorder	DISMB65Y	Strong	Biomarker	[4]
Alpha-1 antitrypsin deficiency	DISQKEHW	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[6]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[7]
Autosomal dominant nocturnal frontal lobe epilepsy	DISE3C4O	Strong	Biomarker	[8]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[9]
Chronic bronchitis	DISS8O8V	Strong	Genetic Variation	[10]
Cocaine addiction	DISHTRXG	Strong	Genetic Variation	[3]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Strong	Genetic Variation	[11]
Dysautonomia	DISF4MT6	Strong	Genetic Variation	[11]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[13]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[14]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[15]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[15]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[17]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[18]
Obesity	DIS47Y1K	Strong	Genetic Variation	[19]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[2]
Pulmonary emphysema	DIS5M7HZ	Strong	Biomarker	[20]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[12]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[21]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[22]
Lung neoplasm	DISVARNB	moderate	Biomarker	[23]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[24]
Squamous cell carcinoma	DISQVIFL	moderate	Genetic Variation	[25]
Coronary heart disease	DIS5OIP1	Disputed	Genetic Variation	[26]
Nicotine dependence	DISZD9W7	Disputed	Genetic Variation	[27]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[31]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[32]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[33]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[34]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[35]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[37]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[39]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Neuronal acetylcholine receptor subunit alpha-3 (CHRNA3).	[40]

References

• [1] Association of the CHRNA3 locus with lung cancer risk and prognosis in Chinese Han population.J Thorac Oncol. 2010 May;5(5):658-66. doi: 10.1097/JTO.0b013e3181d5e447.
• [2] Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers.J Intern Med. 2016 Apr;279(4):388-98. doi: 10.1111/joim.12454. Epub 2015 Dec 22.
• [3] Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence.Hum Mol Genet. 2014 Feb 1;23(3):810-9. doi: 10.1093/hmg/ddt463. Epub 2013 Sep 20.
• [4] Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence.Mol Psychiatry. 2009 May;14(5):501-10. doi: 10.1038/mp.2008.42. Epub 2008 Apr 15.
• [5] Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.Respir Res. 2012 Feb 22;13(1):16. doi: 10.1186/1465-9921-13-16.
• [6] Association of novel and established polymorphisms in neuronal nicotinic acetylcholine receptors with sporadic Alzheimer's disease.J Alzheimers Dis. 2002 Apr;4(2):71-6. doi: 10.3233/jad-2002-4201.
• [7] Pleiotropic effects of Chr15q25 nicotinic gene cluster and the relationship between smoking, cognition and ADHD.J Psychiatr Res. 2016 Sep;80:73-78. doi: 10.1016/j.jpsychires.2016.06.002. Epub 2016 Jun 4.
• [8] Refined mapping of CHRNA3/A5/B4 gene cluster and its implications in ADNFLE.Neuroreport. 2000 Jul 14;11(10):2097-101. doi: 10.1097/00001756-200007140-00008.
• [9] Nicotine activates YAP1 through nAChRs mediated signaling in esophageal squamous cell cancer (ESCC).PLoS One. 2014 Mar 12;9(3):e90836. doi: 10.1371/journal.pone.0090836. eCollection 2014.
• [10] Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease.Respir Res. 2014 Sep 21;15(1):113. doi: 10.1186/s12931-014-0113-2.
• [11] CAKUT and Autonomic Dysfunction Caused by Acetylcholine Receptor Mutations.Am J Hum Genet. 2019 Dec 5;105(6):1286-1293. doi: 10.1016/j.ajhg.2019.10.004. Epub 2019 Nov 7.
• [12] Aberrant DNA methylation of cancer-associated genes in gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).Cancer Lett. 2011 Dec 1;311(1):85-95. doi: 10.1016/j.canlet.2011.06.038. Epub 2011 Jul 14.
• [13] Aberrant DNA methylation distinguishes hepatocellular carcinoma associated with HBV and HCV infection and alcohol intake.J Hepatol. 2011 Apr;54(4):705-15. doi: 10.1016/j.jhep.2010.07.027. Epub 2010 Sep 25.
• [14] CHRNA3 polymorphism modifies lung adenocarcinoma risk in the Chinese Han population.Int J Mol Sci. 2014 Mar 28;15(4):5446-57. doi: 10.3390/ijms15045446.
• [15] Association Between Nicotine-dependent Gene Polymorphism and Smoking Cessation in Patients With Lung Cancer.Clin Lung Cancer. 2020 Mar;21(2):171-176. doi: 10.1016/j.cllc.2019.07.002. Epub 2019 Jul 17.
• [16] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [17] Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand.Cancer Causes Control. 2012 Dec;23(12):1995-2002. doi: 10.1007/s10552-012-0077-9. Epub 2012 Oct 21.
• [18] Study on polymorphisms in CHRNA5/CHRNA3/CHRNB4 gene cluster and the associated with the risk of non-small cell lung cancer.Oncotarget. 2017 Dec 20;9(2):2435-2444. doi: 10.18632/oncotarget.23459. eCollection 2018 Jan 5.
• [19] Heavier smoking may lead to a relative increase in waist circumference: evidence for a causal relationship from a Mendelian randomisation meta-analysis. The CARTA consortium.BMJ Open. 2015 Aug 11;5(8):e008808. doi: 10.1136/bmjopen-2015-008808.
• [20] CHRNA3 variant for lung cancer is associated with chronic obstructive pulmonary disease in Korea.Respiration. 2013;86(2):117-22. doi: 10.1159/000342976. Epub 2012 Nov 27.
• [21] Relationship between CYP2A6 genetic polymorphism, as a marker of nicotine metabolism, and ulcerative colitis.Isr Med Assoc J. 2011 Feb;13(2):87-90.
• [22] CHRNA3 rs6495308 genotype as an effect modifier of the association between daily cigarette consumption and hypertension in Chinese male smokers.Int J Environ Res Public Health. 2015 Apr 14;12(4):4156-69. doi: 10.3390/ijerph120404156.
• [23] Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.Nat Genet. 2008 May;40(5):616-22. doi: 10.1038/ng.109. Epub 2008 Apr 2.
• [24] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [25] Association of smoking with tumor size at diagnosis in non-small cell lung cancer.Lung Cancer. 2011 Dec;74(3):378-83. doi: 10.1016/j.lungcan.2011.04.020. Epub 2011 Jun 8.
• [26] Identifying genetic variants that affect viability in large cohorts.PLoS Biol. 2017 Sep 5;15(9):e2002458. doi: 10.1371/journal.pbio.2002458. eCollection 2017 Sep.
• [27] Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women.BMC Med Genet. 2018 Apr 5;19(1):55. doi: 10.1186/s12881-018-0571-3.
• [28] Minimal residual disease monitoring in neuroblastoma patients based on the expression of a set of real-time RT-PCR markers in tumor-initiating cells.Oncol Rep. 2013 Apr;29(4):1629-36. doi: 10.3892/or.2013.2286. Epub 2013 Feb 12.
• [29] 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.
• [30] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [31] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [32] 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.
• [33] 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.
• [34] Nicotine-induced Ca2+ signaling and down-regulation of nicotinic acetylcholine receptor subunit expression in the CEM human leukemic T-cell line. Life Sci. 2003 Mar 28;72(18-19):2155-8. doi: 10.1016/s0024-3205(03)00077-8.
• [35] 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.
• [36] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [37] 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.
• [38] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [39] 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.
• [40] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.