Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPL3Z8A)

• DOT Name: ATP-sensitive inward rectifier potassium channel 10 (KCNJ10)
• Synonyms: ATP-dependent inwardly rectifying potassium channel Kir4.1; Inward rectifier K(+) channel Kir1.2; Potassium channel, inwardly rectifying subfamily J member 10
• Gene Name: KCNJ10
• Related Disease:
  EAST syndrome
  Pendred syndrome
  Enlarged vestibular aqueduct syndrome
• UniProt ID: KCJ10_HUMAN
• Pfam ID: PF01007 ; PF17655
• Sequence:
  MTSVAKVYYSQTTQTESRPLMGPGIRRRRVLTKDGRSNVRMEHIADKRFLYLKDLWTTFI
  DMQWRYKLLLFSATFAGTWFLFGVVWYLVAVAHGDLLELDPPANHTPCVVQVHTLTGAFL
  FSLESQTTIGYGFRYISEECPLAIVLLIAQLVLTTILEIFITGTFLAKIARPKKRAETIR
  FSQHAVVASHNGKPCLMIRVANMRKSLLIGCQVTGKLLQTHQTKEGENIRLNQVNVTFQV
  DTASDSPFLILPLTFYHVVDETSPLKDLPLRSGEGDFELVLILSGTVESTSATCQVRTSY
  LPEEILWGYEFTPAISLSASGKYIADFSLFDQVVKVASPSGLRDSTVRYGDPEKLKLEES
  LREQAEKEGSALSVRISNV
• Function: May be responsible for potassium buffering action of glial cells in the brain. 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 and cesium. In the kidney, together with KCNJ16, mediates basolateral K(+) recycling in distal tubules; this process is critical for Na(+) reabsorption at the tubules.
• Tissue Specificity: Expressed in kidney (at protein level).
• KEGG Pathway:
  Gastric acid secretion (hsa04971)
  Huntington disease (hsa05016)
• 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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
EAST syndrome	DISSXDQ8	Definitive	Autosomal recessive	[1]
Pendred syndrome	DISZ1MU8	Supportive	Autosomal recessive	[2]
Enlarged vestibular aqueduct syndrome	DISLGBBO	Disputed	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[4]
Marinol	DM70IK5	Approved	Marinol increases the expression of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-sensitive inward rectifier potassium channel 10 (KCNJ10).	[8]

References

• [1] 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.
• [2] Pendred Syndrome?/ Nonsyndromic Enlarged Vestibular Aqueduct. 1998 Sep 28 [updated 2020 Jun 18]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [5] 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.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.