Details of Drug Off-Target (DOT)

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

• DOT Name: Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7)
• Gene Name: CHRNA7
• Related Disease:
  Complex neurodevelopmental disorder
  Epilepsy
• UniProt ID: ACHA7_HUMAN
• PDB ID: 2MAW; 5AFH; 5AFJ; 5AFK; 5AFL; 5AFM; 5AFN; 7EKI; 7EKP; 7EKT; 7KOO; 7KOQ; 7KOX; 7RPM; 8C9X; 8CAU; 8CE4; 8CI1; 8CI2; 8F4V; 8P1H
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MRCSPGGVWLALAASLLHVSLQGEFQRKLYKELVKNYNPLERPVANDSQPLTVYFSLSLL
  QIMDVDEKNQVLTTNIWLQMSWTDHYLQWNVSEYPGVKTVRFPDGQIWKPDILLYNSADE
  RFDATFHTNVLVNSSGHCQYLPPGIFKSSCYIDVRWFPFDVQHCKLKFGSWSYGGWSLDL
  QMQEADISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRRRTLYYGLNLLIP
  CVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFAST
  MIIVGLSVVVTVIVLQYHHHDPDGGKMPKWTRVILLNWCAWFLRMKRPGEDKVRPACQHK
  QRRCSLASVEMSAVAPPPASNGNLLYIGFRGLDGVHCVPTPDSGVVCGRMACSPTHDEHL
  LHGGQPPEGDPDLAKILEEVRYIANRFRCQDESEAVCSEWKFAACVVDRLCLMAFSVFTI
  ICTIGILMSAPNFVEAVSKDFA
• 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. The channel is blocked by alpha-bungarotoxin.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Cholinergic sy.pse (hsa04725)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Nicotine addiction (hsa05033)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway: Highly calcium permeable postsynaptic nicotinic acetylcholine receptors (R-HSA-629594)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[1]
Epilepsy	DISBB28L	Refuted	Unknown	[2]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cotinine	DMCEZ1B	Approved	Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7) increases the response to substance of Cotinine.	[9]
Lobeline	DMT3KB4	Phase 2	Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7) affects the response to substance of Lobeline.	[9]
GTS-21	DMEN5KA	Phase 2	Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7) increases the response to substance of GTS-21.	[9]
ABT-089	DM8DT7U	Discontinued in Phase 2	Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7) increases the response to substance of ABT-089.	[9]

2 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-7 (CHRNA7).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[7]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[8]
Acetylcholine	DMDF79Z	Approved	Acetylcholine increases the activity of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[9]
Carbachol	DMX9K8F	Approved	Carbachol affects the activity of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[14]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the activity of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[15]
Choline	DM5D9YK	Investigative	Choline increases the activity of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[9]
Methylenedioxymethamphetamine	DMYVU47	Investigative	Methylenedioxymethamphetamine increases the activity of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[16]
Epibatidine	DMAGZD8	Investigative	Epibatidine affects the activity of Neuronal acetylcholine receptor subunit alpha-7 (CHRNA7).	[10]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Effects of cannabidiol on the function of 7-nicotinic acetylcholine receptors. Eur J Pharmacol. 2013 Nov 15;720(1-3):310-9. doi: 10.1016/j.ejphar.2013.10.011. Epub 2013 Oct 18.
• [8] 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.
• [9] Gain of function mutation of the alpha7 nicotinic receptor: distinct pharmacology of the human alpha7V274T variant. Eur J Pharmacol. 1999 Feb 5;366(2-3):301-8. doi: 10.1016/s0014-2999(98)00909-1.
• [10] Counteracting desensitization of human 7-nicotinic acetylcholine receptors with bispyridinium compounds as an approach against organophosphorus poisoning. Toxicol Lett. 2018 Sep 1;293:149-156. doi: 10.1016/j.toxlet.2017.12.005. Epub 2017 Dec 14.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [14] 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.
• [15] 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) enhances invasiveness of lung cancer cells by up-regulating contactin-1 via the alpha7 nicotinic acetylcholine receptor/ERK signaling pathway. Chem Biol Interact. 2009 May 15;179(2-3):154-9. doi: 10.1016/j.cbi.2008.10.042. Epub 2008 Nov 5.
• [16] The effects of 3,4-methylenedioxymethamphetamine (MDMA) on nicotinic receptors: intracellular calcium increase, calpain/caspase 3 activation, and functional upregulation. Toxicol Appl Pharmacol. 2010 May 1;244(3):344-53. doi: 10.1016/j.taap.2010.01.014. Epub 2010 Feb 2.