Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBTT4MC)

• DOT Name: ATP-sensitive inward rectifier potassium channel 14 (KCNJ14)
• Synonyms: Inward rectifier K(+) channel Kir2.4; IRK-4; Potassium channel, inwardly rectifying subfamily J member 14
• Gene Name: KCNJ14
• UniProt ID: KCJ14_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MGLARALRRLSGALDSGDSRAGDEEEAGPGLCRNGWAPAPVQSPVGRRRGRFVKKDGHCN
  VRFVNLGGQGARYLSDLFTTCVDVRWRWMCLLFSCSFLASWLLFGLAFWLIASLHGDLAA
  PPPPAPCFSHVASFLAAFLFALETQTSIGYGVRSVTEECPAAVAAVVLQCIAGCVLDAFV
  VGAVMAKMAKPKKRNETLVFSENAVVALRDHRLCLMWRVGNLRRSHLVEAHVRAQLLQPR
  VTPEGEYIPLDHQDVDVGFDGGTDRIFLVSPITIVHEIDSASPLYELGRAELARADFELV
  VILEGMVEATAMTTQCRSSYLPGELLWGHRFEPVLFQRGSQYEVDYRHFHRTYEVPGTPV
  CSAKELDERAEQASHSLKSSFPGSLTAFCYENELALSCCQEEDEDDETEEGNGVETEDGA
  ASPRVLTPTLALTLPP
• Function: Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. KCNJ14 gives rise to low-conductance channels with a low affinity to the channel blockers Barium and Cesium.
• Tissue Specificity: Expressed preferentially in retina.
• KEGG Pathway:
  Cholinergic sy.pse (hsa04725)
  Oxytocin sig.ling pathway (hsa04921)
• Reactome Pathway:
  Phase 4 - resting membrane potential (R-HSA-5576886)
  Classical Kir channels (R-HSA-1296053)

Molecular Interaction Atlas (MIA) of This DOT

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 ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[2]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[6]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of ATP-sensitive inward rectifier potassium channel 14 (KCNJ14).	[8]

References

• [1] 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.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [4] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] 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.