Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYN1E1R)

• DOT Name: ATP-sensitive inward rectifier potassium channel 12 (KCNJ12)
• Synonyms: Inward rectifier K(+) channel Kir2.2; IRK-2; Inward rectifier K(+) channel Kir2.2v; Potassium channel, inwardly rectifying subfamily J member 12
• Gene Name: KCNJ12
• Related Disease:
  Andersen-Tawil syndrome
  Dilated cardiomyopathy 1A
  Familial dilated cardiomyopathy
  Glycogen storage disease due to glycogen branching enzyme deficiency
  Neoplasm
  Hirschsprung disease
• UniProt ID: KCJ12_HUMAN
• Pfam ID: PF01007 ; PF17655 ; PF08466
• Sequence:
  MTAASRANPYSIVSSEEDGLHLVTMSGANGFGNGKVHTRRRCRNRFVKKNGQCNIEFANM
  DEKSQRYLADMFTTCVDIRWRYMLLIFSLAFLASWLLFGIIFWVIAVAHGDLEPAEGRGR
  TPCVMQVHGFMAAFLFSIETQTTIGYGLRCVTEECPVAVFMVVAQSIVGCIIDSFMIGAI
  MAKMARPKKRAQTLLFSHNAVVALRDGKLCLMWRVGNLRKSHIVEAHVRAQLIKPRVTEE
  GEYIPLDQIDIDVGFDKGLDRIFLVSPITILHEIDEASPLFGISRQDLETDDFEIVVILE
  GMVEATAMTTQARSSYLANEILWGHRFEPVLFEEKNQYKIDYSHFHKTYEVPSTPRCSAK
  DLVENKFLLPSANSFCYENELAFLSRDEEDEADGDQDGRSRDGLSPQARHDFDRLQAGGG
  VLEQRPYRRESEI
• Function: Inward rectifying potassium channel that is activated by phosphatidylinositol 4,5-bisphosphate and that probably participates in controlling the resting membrane potential in electrically excitable cells. Probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. 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.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Andersen-Tawil syndrome	DIS3IWZ7	Strong	Biomarker	[1]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[2]
Familial dilated cardiomyopathy	DISBHDU9	Strong	Genetic Variation	[2]
Glycogen storage disease due to glycogen branching enzyme deficiency	DIS3H8HJ	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[5]

2 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 12 (KCNJ12).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-sensitive inward rectifier potassium channel 12 (KCNJ12).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-sensitive inward rectifier potassium channel 12 (KCNJ12).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of ATP-sensitive inward rectifier potassium channel 12 (KCNJ12).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ATP-sensitive inward rectifier potassium channel 12 (KCNJ12).	[9]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of ATP-sensitive inward rectifier potassium channel 12 (KCNJ12).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of ATP-sensitive inward rectifier potassium channel 12 (KCNJ12).	[11]

References

• [1] Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome.Proc Natl Acad Sci U S A. 2002 May 28;99(11):7774-9. doi: 10.1073/pnas.102609499.
• [2] Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated cardiomyopathy.Medicine (Baltimore). 2017 Aug;96(33):e7727. doi: 10.1097/MD.0000000000007727.
• [3] A glutamate residue at the C terminus regulates activity of inward rectifier K+ channels: implication for Andersen's syndrome.Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8430-5. doi: 10.1073/pnas.122682899. Epub 2002 May 28.
• [4] Distribution and association study in copy number variation of KCNJ12 gene across four Chinese cattle populations.Gene. 2019 Mar 20;689:90-96. doi: 10.1016/j.gene.2018.12.019. Epub 2018 Dec 17.
• [5] Sotos syndrome associated with Hirschsprung's disease: a new case and exome-sequencing analysis.Pediatr Res. 2017 Jul;82(1):87-92. doi: 10.1038/pr.2017.106. Epub 2017 May 3.
• [6] 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.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [11] 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.
• [12] 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.