Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE5XENW)

• DOT Name: Neuronal acetylcholine receptor subunit beta-3 (CHRNB3)
• Gene Name: CHRNB3
• Related Disease:
  Bipolar disorder
  Advanced cancer
  Alcohol dependence
  Attention deficit hyperactivity disorder
  Cocaine addiction
  Depression
  Epilepsy, idiopathic generalized
  Esophageal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Non-small-cell lung cancer
  Parkinson disease
• UniProt ID: ACHB3_HUMAN
• PDB ID: 8A5U
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MLPDFMLVLIVLGIPSSATTGFNSIAENEDALLRHLFQGYQKWVRPVLHSNDTIKVYFGL
  KISQLVDVDEKNQLMTTNVWLKQEWTDHKLRWNPDDYGGIHSIKVPSESLWLPDIVLFEN
  ADGRFEGSLMTKVIVKSNGTVVWTPPASYKSSCTMDVTFFPFDRQNCSMKFGSWTYDGTM
  VDLILINENVDRKDFFDNGEWEILNAKGMKGNRRDGVYSYPFITYSFVLRRLPLFYTLFL
  IIPCLGLSFLTVLVFYLPSDEGEKLSLSTSVLVSLTVFLLVIEEIIPSSSKVIPLIGEYL
  LFIMIFVTLSIIVTVFVINVHHRSSSTYHPMAPWVKRLFLQKLPKLLCMKDHVDRYSSPE
  KEESQPVVKGKVLEKKKQKQLSDGEKVLVAFLEKAADSIRYISRHVKKEHFISQVVQDWK
  FVAQVLDRIFLWLFLIVSVTGSVLIFTPALKMWLHSYH
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Cocaine addiction	DISHTRXG	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Genetic Variation	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[8]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[9]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[9]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Neuronal acetylcholine receptor subunit beta-3 (CHRNB3).	[11]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Neuronal acetylcholine receptor subunit beta-3 (CHRNB3).	[12]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Neuronal acetylcholine receptor subunit beta-3 (CHRNB3).	[13]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Neuronal acetylcholine receptor subunit beta-3 (CHRNB3).	[14]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Neuronal acetylcholine receptor subunit beta-3 (CHRNB3).	[17]

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 decreases the methylation of Neuronal acetylcholine receptor subunit beta-3 (CHRNB3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neuronal acetylcholine receptor subunit beta-3 (CHRNB3).	[16]

References

• [1] Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy.Sci Rep. 2014 Mar 28;4:4497. doi: 10.1038/srep04497.
• [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] A functional U-statistic method for association analysis of sequencing data.Genet Epidemiol. 2017 Nov;41(7):636-643. doi: 10.1002/gepi.22063. Epub 2017 Aug 29.
• [4] Nicotinic receptor gene variants interact with attention deficient hyperactive disorder symptoms to predict smoking trajectories from early adolescence to adulthood.Addict Behav. 2013 Nov;38(11):2683-9. doi: 10.1016/j.addbeh.2013.06.013. Epub 2013 Jul 1.
• [5] 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.
• [6] Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer.Mol Psychiatry. 2009 Jun;14(6):563-89. doi: 10.1038/mp.2009.2. Epub 2009 Feb 10.
• [7] Evidence for linkage of adolescent-onset idiopathic generalized epilepsies to chromosome 8-and genetic heterogeneity.Am J Hum Genet. 1999 May;64(5):1411-9. doi: 10.1086/302371.
• [8] A genetic variant in CHRNB3-CHRNA6 increases risk of esophageal squamous cell carcinoma in Chinese populations.Carcinogenesis. 2015 May;36(5):538-42. doi: 10.1093/carcin/bgv019. Epub 2015 Mar 30.
• [9] Genetic variants of CHRNA5-A3 and CHRNB3-A6 predict survival of patients with advanced non-small cell lung cancer.Oncotarget. 2016 May 3;7(18):26436-43. doi: 10.18632/oncotarget.8510.
• [10] CHRNB3 c.-57A>G functional promoter change affects Parkinson's disease and smoking.Neurobiol Aging. 2014 Sep;35(9):2179.e1-6. doi: 10.1016/j.neurobiolaging.2014.03.014. Epub 2014 Mar 20.
• [11] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [12] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [13] 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.
• [14] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [15] 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.
• [16] 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.
• [17] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.