Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZT6EQB)

• DOT Name: ATP-sensitive inward rectifier potassium channel 15 (KCNJ15)
• Synonyms: Inward rectifier K(+) channel Kir1.3; Inward rectifier K(+) channel Kir4.2; Potassium channel, inwardly rectifying subfamily J member 15
• Gene Name: KCNJ15
• Related Disease:
  Hyperinsulinemia
  Juvenile idiopathic arthritis
  Non-insulin dependent diabetes
  Acute myelogenous leukaemia
• UniProt ID: KCJ15_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MDAIHIGMSSTPLVKHTAGAGLKANRPRVMSKSGHSNVRIDKVDGIYLLYLQDLWTTVID
  MKWRYKLTLFAATFVMTWFLFGVIYYAIAFIHGDLEPGEPISNHTPCIMKVDSLTGAFLF
  SLESQTTIGYGVRSITEECPHAIFLLVAQLVITTLIEIFITGTFLAKIARPKKRAETIKF
  SHCAVITKQNGKLCLVIQVANMRKSLLIQCQLSGKLLQTHVTKEGERILLNQATVKFHVD
  SSSESPFLILPMTFYHVLDETSPLRDLTPQNLKEKEFELVVLLNATVESTSAVCQSRTSY
  IPEEIYWGFEFVPVVSLSKNGKYVADFSQFEQIRKSPDCTFYCADSEKQQLEEKYRQEDQ
  RERELRTLLLQQSNV
• 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.
• KEGG Pathway: Gastric acid secretion (hsa04971)
• 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
Hyperinsulinemia	DISIDWT6	Strong	Altered Expression	[1]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[10]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate increases the activity of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[11]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-sensitive inward rectifier potassium channel 15 (KCNJ15).	[13]

References

• [1] Inhibition of glucose-stimulated insulin secretion by KCNJ15, a newly identified susceptibility gene for type 2 diabetes.Diabetes. 2012 Jul;61(7):1734-41. doi: 10.2337/db11-1201. Epub 2012 May 7.
• [2] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [3] Replication study for the association of a single-nucleotide polymorphism, rs3746876, within KCNJ15, with susceptibility to type 2 diabetes in a Japanese population.J Hum Genet. 2013 Jul;58(7):490-3. doi: 10.1038/jhg.2013.28. Epub 2013 Apr 18.
• [4] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Changes in gene expression profiles in response to selenium supplementation among individuals with arsenic-induced pre-malignant skin lesions. Toxicol Lett. 2007 Mar 8;169(2):162-76. doi: 10.1016/j.toxlet.2007.01.006. Epub 2007 Jan 19.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [11] An inwardly rectifying potassium channel in apical membrane of Calu-3 cells. J Biol Chem. 2004 Nov 5;279(45):46558-65. doi: 10.1074/jbc.M406058200. Epub 2004 Aug 24.
• [12] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.