Details of Drug Off-Target (DOT)

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

• DOT Name: Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2)
• Gene Name: CHRNA2
• Related Disease:
  Autosomal dominant nocturnal frontal lobe epilepsy 4
  Autosomal dominant nocturnal frontal lobe epilepsy
  Benign familial infantile epilepsy
  Sleep-related hypermotor epilepsy
• UniProt ID: ACHA2_HUMAN
• PDB ID: 5FJV
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MGPSCPVFLSFTKLSLWWLLLTPAGGEEAKRPPPRAPGDPLSSPSPTALPQGGSHTETED
  RLFKHLFRGYNRWARPVPNTSDVVIVRFGLSIAQLIDVDEKNQMMTTNVWLKQEWSDYKL
  RWNPTDFGNITSLRVPSEMIWIPDIVLYNNADGEFAVTHMTKAHLFSTGTVHWVPPAIYK
  SSCSIDVTFFPFDQQNCKMKFGSWTYDKAKIDLEQMEQTVDLKDYWESGEWAIVNATGTY
  NSKKYDCCAEIYPDVTYAFVIRRLPLFYTINLIIPCLLISCLTVLVFYLPSDCGEKITLC
  ISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVITVFVLNVHHRSPSTH
  TMPHWVRGALLGCVPRWLLMNRPPPPVELCHPLRLKLSPSYHWLESNVDAEEREVVVEEE
  DRWACAGHVAPSVGTLCSHGHLHSGASGPKAEALLQEGELLLSPHMQKALEGVHYIADHL
  RSEDADSSVKEDWKYVAMVIDRIFLWLFIIVCFLGTIGLFLPPFLAGMI
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant nocturnal frontal lobe epilepsy 4	DIS8N0WD	Strong	Autosomal dominant	[1]
Autosomal dominant nocturnal frontal lobe epilepsy	DISE3C4O	Supportive	Autosomal dominant	[1]
Benign familial infantile epilepsy	DISFYXOW	Disputed	Autosomal dominant	[2]
Sleep-related hypermotor epilepsy	DISWP477	Limited	Autosomal dominant	[2]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2) affects the response to substance of Carbamazepine.	[6]
Nicotine	DMWX5CO	Approved	Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2) affects the response to substance of Nicotine.	[6]
Acetylcholine	DMDF79Z	Approved	Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2) affects the response to substance of Acetylcholine.	[6]

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-2 (CHRNA2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2).	[4]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Neuronal acetylcholine receptor subunit alpha-2 (CHRNA2).	[4]

References

• [1] Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet. 2006 Aug;79(2):342-50. doi: 10.1086/506459. Epub 2006 Jun 26.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [5] 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.
• [6] Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene. FEBS Lett. 2009 May 19;583(10):1599-604. doi: 10.1016/j.febslet.2009.04.024. Epub 2009 Apr 19.