Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIV4MC1)

• DOT Name: Neuronal acetylcholine receptor subunit beta-4 (CHRNB4)
• Gene Name: CHRNB4
• Related Disease: Lung cancer
• UniProt ID: ACHB4_HUMAN
• PDB ID: 6PV7; 6PV8
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MRRAPSLVLFFLVALCGRGNCRVANAEEKLMDDLLNKTRYNNLIRPATSSSQLISIKLQL
  SLAQLISVNEREQIMTTNVWLKQEWTDYRLTWNSSRYEGVNILRIPAKRIWLPDIVLYNN
  ADGTYEVSVYTNLIVRSNGSVLWLPPAIYKSACKIEVKYFPFDQQNCTLKFRSWTYDHTE
  IDMVLMTPTASMDDFTPSGEWDIVALPGRRTVNPQDPSYVDVTYDFIIKRKPLFYTINLI
  IPCVLTTLLAILVFYLPSDCGEKMTLCISVLLALTFFLLLISKIVPPTSLDVPLIGKYLM
  FTMVLVTFSIVTSVCVLNVHHRSPSTHTMAPWVKRCFLHKLPTFLFMKRPGPDSSPARAF
  PPSKSCVTKPEATATSTSPSNFYGNSMYFVNPASAASKSPAGSTPVAIPRDFWLRSSGRF
  RQDVQEALEGVSFIAQHMKNDDEDQSVVEDWKYVAMVVDRLFLWVFMFVCVLGTVGLFLP
  PLFQTHAASEGPYAAQRD
• 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)
  Neutrophil degranulation (R-HSA-6798695)
  Highly sodium permeable postsynaptic acetylcholine nicotinic receptors (R-HSA-629587)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Limited	Autosomal dominant	[1]

4 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 beta-4 (CHRNB4).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neuronal acetylcholine receptor subunit beta-4 (CHRNB4).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Neuronal acetylcholine receptor subunit beta-4 (CHRNB4).	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Neuronal acetylcholine receptor subunit beta-4 (CHRNB4).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Neuronal acetylcholine receptor subunit beta-4 (CHRNB4).	[3]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Neuronal acetylcholine receptor subunit beta-4 (CHRNB4).	[5]

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] 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.
• [3] 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.
• [4] 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.
• [5] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [6] 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.
• [7] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.