Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2OQEZS)

• DOT Name: Inward rectifier potassium channel 2 (KCNJ2)
• Synonyms: Cardiac inward rectifier potassium channel; Inward rectifier K(+) channel Kir2.1; IRK-1; hIRK1; Potassium channel, inwardly rectifying subfamily J member 2
• Gene Name: KCNJ2
• Related Disease:
  Andersen-Tawil syndrome
  Short QT syndrome type 3
  Short QT syndrome
  Familial atrial fibrillation
  Catecholaminergic polymorphic ventricular tachycardia
  Long QT syndrome
• UniProt ID: KCNJ2_HUMAN
• PDB ID: 6SPZ; 7ZDZ
• Pfam ID: PF01007 ; PF17655 ; PF08466
• Sequence:
  MGSVRTNRYSIVSSEEDGMKLATMAVANGFGNGKSKVHTRQQCRSRFVKKDGHCNVQFIN
  VGEKGQRYLADIFTTCVDIRWRWMLVIFCLAFVLSWLFFGCVFWLIALLHGDLDASKEGK
  ACVSEVNSFTAAFLFSIETQTTIGYGFRCVTDECPIAVFMVVFQSIVGCIIDAFIIGAVM
  AKMAKPKKRNETLVFSHNAVIAMRDGKLCLMWRVGNLRKSHLVEAHVRAQLLKSRITSEG
  EYIPLDQIDINVGFDSGIDRIFLVSPITIVHEIDEDSPLYDLSKQDIDNADFEIVVILEG
  MVEATAMTTQCRSSYLANEILWGHRYEPVLFEEKHYYKVDYSRFHKTYEVPNTPLCSARD
  LAEKKYILSNANSFCYENEVALTSKEEDDSENGVPESTSTDTPPDIDLHNQASVPLEPRP
  LRRESEI
• Function: 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. Can be blocked by extracellular barium or cesium.
• Tissue Specificity: Heart, brain, placenta, lung, skeletal muscle, and kidney. Diffusely distributed throughout the brain.
• KEGG Pathway:
  Cholinergic sy.pse (hsa04725)
  Oxytocin sig.ling pathway (hsa04921)
  Renin secretion (hsa04924)
  Gastric acid secretion (hsa04971)
• Reactome Pathway:
  Classical Kir channels (R-HSA-1296053)
  Phase 4 - resting membrane potential (R-HSA-5576886)
  Sensory perception of sour taste (R-HSA-9729555)
  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	Definitive	Autosomal dominant	[1]
Short QT syndrome type 3	DIST7UL9	Strong	Autosomal dominant	[2]
Short QT syndrome	DISOI9X1	Moderate	Autosomal dominant	[3]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[4]
Catecholaminergic polymorphic ventricular tachycardia	DISSAS1A	Disputed	Autosomal dominant	[3]
Long QT syndrome	DISMKWS3	Limited	Autosomal dominant	[3]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Propranolol	DM79NTF	Approved	Inward rectifier potassium channel 2 (KCNJ2) affects the response to substance of Propranolol.	[24]
Atenolol	DMNKG1Z	Approved	Inward rectifier potassium channel 2 (KCNJ2) affects the response to substance of Atenolol.	[24]

23 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 2 (KCNJ2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[11]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[12]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[15]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[7]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[16]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[11]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[20]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Inward rectifier potassium channel 2 (KCNJ2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Inward rectifier potassium channel 2 (KCNJ2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Inward rectifier potassium channel 2 (KCNJ2).	[14]

References

• [1] Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest. 2002 Aug;110(3):381-8. doi: 10.1172/JCI15183.
• [2] A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005 Apr 15;96(7):800-7. doi: 10.1161/01.RES.0000162101.76263.8c. Epub 2005 Mar 10.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005 Jul 15;332(4):1012-9. doi: 10.1016/j.bbrc.2005.05.054.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [7] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Gene expression profiles in peripheral lymphocytes by arsenic exposure and skin lesion status in a Bangladeshi population. Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1367-75. doi: 10.1158/1055-9965.EPI-06-0106.
• [10] 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.
• [11] 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.
• [12] Functional cardiotoxicity assessment of cosmetic compounds using human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol. 2018 Jan;92(1):371-381.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [19] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [20] 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.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] 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.
• [23] 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.
• [24] Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome. J Cardiovasc Electrophysiol. 2004 Feb;15(2):190-9. doi: 10.1046/j.1540-8167.2004.03212.x.