Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA2MBIE)

• DOT Name: G protein-activated inward rectifier potassium channel 4 (KCNJ5)
• Synonyms: GIRK-4; Cardiac inward rectifier; CIR; Heart KATP channel; Inward rectifier K(+) channel Kir3.4; IRK-4; KATP-1; Potassium channel, inwardly rectifying subfamily J member 5
• Gene Name: KCNJ5
• Related Disease:
  Familial hyperaldosteronism type III
  Andersen-Tawil syndrome
  Long QT syndrome
  Long QT syndrome 13
• UniProt ID: KCNJ5_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MAGDSRNAMNQDMEIGVTPWDPKKIPKQARDYVPIATDRTRLLAEGKKPRQRYMEKSGKC
  NVHHGNVQETYRYLSDLFTTLVDLKWRFNLLVFTMVYTVTWLFFGFIWWLIAYIRGDLDH
  VGDQEWIPCVENLSGFVSAFLFSIETETTIGYGFRVITEKCPEGIILLLVQAILGSIVNA
  FMVGCMFVKISQPKKRAETLMFSNNAVISMRDEKLCLMFRVGDLRNSHIVEASIRAKLIK
  SRQTKEGEFIPLNQTDINVGFDTGDDRLFLVSPLIISHEINQKSPFWEMSQAQLHQEEFE
  VVVILEGMVEATGMTCQARSSYMDTEVLWGHRFTPVLTLEKGFYEVDYNTFHDTYETNTP
  SCCAKELAEMKREGRLLQYLPSPPLLGGCAEAGLDAEAEQNEEDEPKGLGGSREARGSV
• Function: This potassium channel is controlled by G proteins. 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 external barium.
• Tissue Specificity: Islets, exocrine pancreas and heart. Expressed in the adrenal cortex, particularly the zona glomerulosa.
• KEGG Pathway:
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Serotonergic sy.pse (hsa04726)
  Dopaminergic sy.pse (hsa04728)
  Estrogen sig.ling pathway (hsa04915)
  Oxytocin sig.ling pathway (hsa04921)
  Aldosterone synthesis and secretion (hsa04925)
  GnRH secretion (hsa04929)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial hyperaldosteronism type III	DISFCXXZ	Strong	Autosomal dominant	[1]
Andersen-Tawil syndrome	DIS3IWZ7	Supportive	Autosomal dominant	[2]
Long QT syndrome	DISMKWS3	Disputed	Autosomal dominant	[3]
Long QT syndrome 13	DISXC8UD	Limited	Autosomal dominant	[4]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aldosterone	DM9S2JW	Approved	G protein-activated inward rectifier potassium channel 4 (KCNJ5) decreases the secretion of Aldosterone.	[18]

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 G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone affects the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of G protein-activated inward rectifier potassium channel 4 (KCNJ5).	[17]

References

• [1] KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension. 2012 Feb;59(2):235-40. doi: 10.1161/HYPERTENSIONAHA.111.183996. Epub 2011 Dec 27.
• [2] A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. Neurology. 2014 Mar 25;82(12):1058-64. doi: 10.1212/WNL.0000000000000239. Epub 2014 Feb 26.
• [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] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] 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.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Neuronal and cardiac toxicity of pharmacological compounds identified through transcriptomic analysis of human pluripotent stem cell-derived embryoid bodies. Toxicol Appl Pharmacol. 2021 Dec 15;433:115792. doi: 10.1016/j.taap.2021.115792. Epub 2021 Nov 3.
• [12] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] 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.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] 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.
• [17] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.
• [18] The potassium channel, Kir3.4 participates in angiotensin II-stimulated aldosterone production by a human adrenocortical cell line. Endocrinology. 2012 Sep;153(9):4328-35. doi: 10.1210/en.2012-1241. Epub 2012 Jul 13.