Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ2F6VR)

• DOT Name: Inward rectifier potassium channel 4 (KCNJ4)
• Synonyms: HIRK2; HRK1; Hippocampal inward rectifier; HIR; Inward rectifier K(+) channel Kir2.3; IRK-3; Potassium channel, inwardly rectifying subfamily J member 4
• Gene Name: KCNJ4
• UniProt ID: KCNJ4_HUMAN
• PDB ID: 3GJ9
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MHGHSRNGQAHVPRRKRRNRFVKKNGQCNVYFANLSNKSQRYMADIFTTCVDTRWRYMLM
  IFSAAFLVSWLFFGLLFWCIAFFHGDLEASPGVPAAGGPAAGGGGAAPVAPKPCIMHVNG
  FLGAFLFSVETQTTIGYGFRCVTEECPLAVIAVVVQSIVGCVIDSFMIGTIMAKMARPKK
  RAQTLLFSHHAVISVRDGKLCLMWRVGNLRKSHIVEAHVRAQLIKPYMTQEGEYLPLDQR
  DLNVGYDIGLDRIFLVSPIIIVHEIDEDSPLYGMGKEELESEDFEIVVILEGMVEATAMT
  TQARSSYLASEILWGHRFEPVVFEEKSHYKVDYSRFHKTYEVAGTPCCSARELQESKITV
  LPAPPPPPSAFCYENELALMSQEEEEMEEEAAAAAAVAAGLGLEAGSKEEAGIIRMLEFG
  SHLDLERMQASLPLDNISYRRESAI
• 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. Can be blocked by extracellular barium and cesium.
• Tissue Specificity: Heart, skeletal muscle, and several different brain regions including the hippocampus.
• KEGG Pathway:
  Cholinergic sy.pse (hsa04725)
  Oxytocin sig.ling pathway (hsa04921)
• Reactome Pathway:
  Classical Kir channels (R-HSA-1296053)
  Phase 4 - resting membrane potential (R-HSA-5576886)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Inward rectifier potassium channel 4 (KCNJ4).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inward rectifier potassium channel 4 (KCNJ4).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Inward rectifier potassium channel 4 (KCNJ4).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Inward rectifier potassium channel 4 (KCNJ4).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Inward rectifier potassium channel 4 (KCNJ4).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inward rectifier potassium channel 4 (KCNJ4).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Inward rectifier potassium channel 4 (KCNJ4).	[8]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Inward rectifier potassium channel 4 (KCNJ4).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Inward rectifier potassium channel 4 (KCNJ4).	[6]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] 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.
• [7] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [8] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.