Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT174UPV)

• DOT Name: Inward rectifier potassium channel 16 (KCNJ16)
• Synonyms: Inward rectifier K(+) channel Kir5.1; Potassium channel, inwardly rectifying subfamily J member 16
• Gene Name: KCNJ16
• Related Disease:
  EAST syndrome
  Hypokalemic alkalosis, familial, with specific renal tubulopathy
  Hypokalemic tubulopathy and deafness
  Intellectual disability
  Matthew-Wood syndrome
• UniProt ID: KCJ16_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MSYYGSSYHIINADAKYPGYPPEHIIAEKRRARRRLLHKDGSCNVYFKHIFGEWGSYVVD
  IFTTLVDTKWRHMFVIFSLSYILSWLIFGSVFWLIAFHHGDLLNDPDITPCVDNVHSFTG
  AFLFSLETQTTIGYGYRCVTEECSVAVLMVILQSILSCIINTFIIGAALAKMATARKRAQ
  TIRFSYFALIGMRDGKLCLMWRIGDFRPNHVVEGTVRAQLLRYTEDSEGRMTMAFKDLKL
  VNDQIILVTPVTIVHEIDHESPLYALDRKAVAKDNFEILVTFIYTGDSTGTSHQSRSSYV
  PREILWGHRFNDVLEVKRKYYKVNCLQFEGSVEVYAPFCSAKQLDWKDQQLHIEKAPPVR
  ESCTSDTKARRRSFSAVAIVSSCENPEETTTSATHEYRETPYQKALLTLNRISVESQM
• 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. KCNJ16 may be involved in the regulation of fluid and pH balance. In the kidney, together with KCNJ10, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules.
• Tissue Specificity: Widely expressed, with highest levels in adult and fetal kidney (at protein level). In the kidney, expressed in the proximal and distal convoluted tubules, but not in glomeruli nor collecting ducts.
• KEGG Pathway: Gastric acid secretion (hsa04971)
• Reactome Pathway:
  Potassium transport channels (R-HSA-1296067)
  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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
EAST syndrome	DISSXDQ8	Strong	Biomarker	[1]
Hypokalemic alkalosis, familial, with specific renal tubulopathy	DISL94EJ	Strong	Autosomal recessive	[2]
Hypokalemic tubulopathy and deafness	DISTTMHD	Strong	Autosomal recessive	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Inward rectifier potassium channel 16 (KCNJ16).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Inward rectifier potassium channel 16 (KCNJ16).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Inward rectifier potassium channel 16 (KCNJ16).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Inward rectifier potassium channel 16 (KCNJ16).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Inward rectifier potassium channel 16 (KCNJ16).	[10]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Inward rectifier potassium channel 16 (KCNJ16).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Inward rectifier potassium channel 16 (KCNJ16).	[16]

References

• [1] Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome.Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10361-6. doi: 10.1073/pnas.1101400108. Epub 2011 Jun 1.
• [2] 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.
• [3] Variability in a three-generation family with Pierre Robin sequence, acampomelic campomelic dysplasia, and intellectual disability due to a novel ?1 Mb deletion upstream of SOX9, and including KCNJ2 and KCNJ16. Birth Defects Res A Clin Mol Teratol. 2016 Jan;106(1):61-8. doi: 10.1002/bdra.23463. Epub 2015 Dec 11.
• [4] Integrated expression profiling of potassium channels identifys KCNN4 as a prognostic biomarker of pancreatic cancer.Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):113-119. doi: 10.1016/j.bbrc.2017.10.072. Epub 2017 Oct 16.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [10] 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.
• [11] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [12] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [13] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [14] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [15] 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.
• [16] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.