Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT6W86V)

• DOT Name: Neuronal acetylcholine receptor subunit alpha-6 (CHRNA6)
• Gene Name: CHRNA6
• Related Disease:
  Neoplasm
  Analgesia
  Attention deficit hyperactivity disorder
  Bipolar disorder
  Cocaine addiction
  Depression
  Esophageal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Substance withdrawal syndrome
  Psychotic disorder
• UniProt ID: ACHA6_HUMAN
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MLTSKGQGFLHGGLCLWLCVFTPFFKGCVGCATEERLFHKLFSHYNQFIRPVENVSDPVT
  VHFEVAITQLANVDEVNQIMETNLWLRHIWNDYKLRWDPMEYDGIETLRVPADKIWKPDI
  VLYNNAVGDFQVEGKTKALLKYNGMITWTPPAIFKSSCPMDITFFPFDHQNCSLKFGSWT
  YDKAEIDLLIIGSKVDMNDFWENSEWEIIDASGYKHDIKYNCCEEIYTDITYSFYIRRLP
  MFYTINLIIPCLFISFLTVLVFYLPSDCGEKVTLCISVLLSLTVFLLVITETIPSTSLVV
  PLVGEYLLFTMIFVTLSIVVTVFVLNIHYRTPTTHTMPRWVKTVFLKLLPQVLLMRWPLD
  KTRGTGSDAVPRGLARRPAKGKLASHGEPRHLKECFHCHKSNELATSKRRLSHQPLQWVV
  ENSEHSPEVEDVINSVQFIAENMKSHNETKEVEDDWKYVAMVVDRVFLWVFIIVCVFGTA
  GLFLQPLLGNTGKS
• 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)
  Nicotine addiction (hsa05033)
• 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

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Analgesia	DISK3TVI	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[4]
Cocaine addiction	DISHTRXG	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[7]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[8]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[8]
Substance withdrawal syndrome	DISTT24U	Strong	Biomarker	[9]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Neuronal acetylcholine receptor subunit alpha-6 (CHRNA6).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neuronal acetylcholine receptor subunit alpha-6 (CHRNA6).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Neuronal acetylcholine receptor subunit alpha-6 (CHRNA6).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Neuronal acetylcholine receptor subunit alpha-6 (CHRNA6).	[13]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Neuronal acetylcholine receptor subunit alpha-6 (CHRNA6).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Neuronal acetylcholine receptor subunit alpha-6 (CHRNA6).	[16]

References

• [1] Molecular profiles of non-small cell lung cancers in cigarette smoking and never-smoking patients.Adv Med Sci. 2013;58(2):196-206. doi: 10.2478/ams-2013-0025.
• [2] The nicotinic 6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors.Sci Transl Med. 2015 May 13;7(287):287ra72. doi: 10.1126/scitranslmed.3009986.
• [3] 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.
• [4] Genetic association of bipolar disorder with the (3) nicotinic receptor subunit gene.Psychiatr Genet. 2011 Apr;21(2):77-84. doi: 10.1097/YPG.0b013e32834135eb.
• [5] Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans.Addiction. 2014 May;109(5):814-22. doi: 10.1111/add.12478. Epub 2014 Feb 18.
• [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] 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.
• [8] Combined effect between CHRNB3-CHRNA6 region gene variant (rs6474412) and smoking in psoriasis vulgaris severity.Gene. 2014 Jul 10;544(2):123-7. doi: 10.1016/j.gene.2014.04.070. Epub 2014 Apr 30.
• [9] The role of alpha6-containing nicotinic acetylcholine receptors in nicotine reward and withdrawal.J Pharmacol Exp Ther. 2009 Nov;331(2):547-54. doi: 10.1124/jpet.109.155457. Epub 2009 Jul 30.
• [10] Effects of repeated long-term psychosocial stress and acute cannabinoid exposure on mouse corticostriatal circuitries: Implications for neuropsychiatric disorders.CNS Neurosci Ther. 2018 Jun;24(6):528-538. doi: 10.1111/cns.12810. Epub 2018 Jan 31.
• [11] 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.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [14] 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.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.