Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT2ECCW)

• DOT Name: Protein cornichon homolog 2 (CNIH2)
• Synonyms: CNIH-2; Cornichon family AMPA receptor auxiliary protein 2; Cornichon-like protein
• Gene Name: CNIH2
• Related Disease:
  Type-1/2 diabetes
  Gout
• UniProt ID: CNIH2_HUMAN
• PDB ID: 8SS2; 8SS3; 8SS4; 8SS6; 8SS7; 8SSA; 8SSB
• Pfam ID: PF03311
• Sequence:
  MAFTFAAFCYMLTLVLCASLIFFVIWHIIAFDELRTDFKNPIDQGNPARARERLKNIERI
  CCLLRKLVVPEYSIHGLFCLMFLCAAEWVTLGLNIPLLFYHLWRYFHRPADGSEVMYDAV
  SIMNADILNYCQKESWCKLAFYLLSFFYYLYSMVYTLVSF
• 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. Blocks CACNG8-mediated resensitization of AMPA receptors.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[1]
Gout	DISHC0U7	Limited	Genetic Variation	[2]

3 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 Protein cornichon homolog 2 (CNIH2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein cornichon homolog 2 (CNIH2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein cornichon homolog 2 (CNIH2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein cornichon homolog 2 (CNIH2).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein cornichon homolog 2 (CNIH2).	[5]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Protein cornichon homolog 2 (CNIH2).	[6]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Protein cornichon homolog 2 (CNIH2).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein cornichon homolog 2 (CNIH2).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Protein cornichon homolog 2 (CNIH2).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Protein cornichon homolog 2 (CNIH2).	[11]

References

• [1] Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.Ann Rheum Dis. 2016 Apr;75(4):652-9. doi: 10.1136/annrheumdis-2014-206191. Epub 2015 Feb 2.
• [2] GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.Ann Rheum Dis. 2017 May;76(5):869-877. doi: 10.1136/annrheumdis-2016-209632. Epub 2016 Nov 29.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [7] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [8] 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.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [10] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [11] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.