Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNLZ2QS)

• DOT Name: Protein cornichon homolog 3 (CNIH3)
• Synonyms: CNIH-3; Cornichon family AMPA receptor auxiliary protein 3
• Gene Name: CNIH3
• Related Disease:
  Advanced cancer
  Schizophrenia
  Alcohol dependence
  Endometriosis
  Opioid dependence
• UniProt ID: CNIH3_HUMAN
• Pfam ID: PF03311
• Sequence:
  MAFTFAAFCYMLSLVLCAALIFFAIWHIIAFDELRTDFKSPIDQCNPVHARERLRNIERI
  CFLLRKLVLPEYSIHSLFCIMFLCAQEWLTLGLNVPLLFYHFWRYFHCPADSSELAYDPP
  VVMNADTLSYCQKEAWCKLAFYLLSFFYYLYCMIYTLVSS
• Function: Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by regulating their rates of activation, deactivation and desensitization.
• Tissue Specificity: Expression is up-regulated in dorsolateral prefrontal cortex of patients with schizophrenia (postmortem brain study).
• Reactome Pathway:
  Cargo concentration in the ER (R-HSA-5694530)
  COPII-mediated vesicle transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[3]
Endometriosis	DISX1AG8	Disputed	Biomarker	[4]
Opioid dependence	DIS6WEHK	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Protein cornichon homolog 3 (CNIH3).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein cornichon homolog 3 (CNIH3).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein cornichon homolog 3 (CNIH3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein cornichon homolog 3 (CNIH3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein cornichon homolog 3 (CNIH3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Protein cornichon homolog 3 (CNIH3).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Protein cornichon homolog 3 (CNIH3).	[12]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Protein cornichon homolog 3 (CNIH3).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Protein cornichon homolog 3 (CNIH3).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Protein cornichon homolog 3 (CNIH3).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein cornichon homolog 3 (CNIH3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein cornichon homolog 3 (CNIH3).	[14]

1 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 increases the methylation of Protein cornichon homolog 3 (CNIH3).	[16]

References

• [1] Cancer risk susceptibility loci in a Swedish population.Oncotarget. 2017 Nov 25;8(66):110300-110310. doi: 10.18632/oncotarget.22687. eCollection 2017 Dec 15.
• [2] Upregulation of cornichon transcripts in the dorsolateral prefrontal cortex in schizophrenia.Neuroreport. 2012 Dec 5;23(17):1031-4. doi: 10.1097/WNR.0b013e32835ad229.
• [3] Evidence of CNIH3 involvement in opioid dependence.Mol Psychiatry. 2016 May;21(5):608-14. doi: 10.1038/mp.2015.102. Epub 2015 Aug 4.
• [4] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [5] Structural basis for preferential binding of human TCF4 to DNA containing 5-carboxylcytosine.Nucleic Acids Res. 2019 Sep 19;47(16):8375-8387. doi: 10.1093/nar/gkz381.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] 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.
• [10] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [13] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] 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.
• [16] 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.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.