Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT68V64E)

• DOT Name: Potassium channel subfamily K member 5 (KCNK5)
• Synonyms: Acid-sensitive potassium channel protein TASK-2; TWIK-related acid-sensitive K(+) channel 2
• Gene Name: KCNK5
• Related Disease:
  Nephropathy
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Central hypoventilation syndrome, congenital
  Coronary heart disease
  Epilepsy
  Multiple sclerosis
  Primary aldosteronism
  Status epilepticus seizure
  Migraine disorder
  Psychotic disorder
  Schizophrenia
• UniProt ID: KCNK5_HUMAN
• Pfam ID: PF07885
• Sequence:
  MVDRGPLLTSAIIFYLAIGAAIFEVLEEPHWKEAKKNYYTQKLHLLKEFPCLGQEGLDKI
  LEVVSDAAGQGVAITGNQTFNNWNWPNAMIFAATVITTIGYGNVAPKTPAGRLFCVFYGL
  FGVPLCLTWISALGKFFGGRAKRLGQFLTKRGVSLRKAQITCTVIFIVWGVLVHLVIPPF
  VFMVTEGWNYIEGLYYSFITISTIGFGDFVAGVNPSANYHALYRYFVELWIYLGLAWLSL
  FVNWKVSMFVEVHKAIKKRRRRRKESFESSPHSRKALQVKGSTASKDVNIFSFLSKKEET
  YNDLIKQIGKKAMKTSGGGETGPGPGLGPQGGGLPALPPSLVPLVVYSKNRVPTLEEVSQ
  TLRSKGHVSRSPDEEAVARAPEDSSPAPEVFMNQLDRISEECEPWDAQDYHPLIFQDASI
  TFVNTEAGLSDEETSKSSLEDNLAGEESPQQGAEAKAPLNMGEFPSSSESTFTSTESELS
  VPYEQLMNEYNKANSPKGT
• Function: pH-dependent, outwardly rectifying potassium channel. Outward rectification is lost at high external K(+) concentrations.
• Tissue Specificity: Abundant expression in kidney, also detected in liver, placenta and small intestine. In the kidney, expression is restricted to the distal tubules and collecting ducts . Not expressed in proximal tubules or glomeruli .
• KEGG Pathway:
  Taste transduction (hsa04742)
  Protein digestion and absorption (hsa04974)
• Reactome Pathway: Phase 4 - resting membrane potential (R-HSA-5576886)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Central hypoventilation syndrome, congenital	DISQRK53	Strong	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[5]
Epilepsy	DISBB28L	Strong	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[7]
Primary aldosteronism	DISOEFNH	Strong	Genetic Variation	[8]
Status epilepticus seizure	DISY3BIC	Strong	Biomarker	[9]
Migraine disorder	DISFCQTG	Limited	Genetic Variation	[10]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[11]
Schizophrenia	DISSRV2N	Limited	Biomarker	[11]

10 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 Potassium channel subfamily K member 5 (KCNK5).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Potassium channel subfamily K member 5 (KCNK5).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Potassium channel subfamily K member 5 (KCNK5).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Potassium channel subfamily K member 5 (KCNK5).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Potassium channel subfamily K member 5 (KCNK5).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Potassium channel subfamily K member 5 (KCNK5).	[18]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Potassium channel subfamily K member 5 (KCNK5).	[18]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Potassium channel subfamily K member 5 (KCNK5).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Potassium channel subfamily K member 5 (KCNK5).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Potassium channel subfamily K member 5 (KCNK5).	[22]

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 Potassium channel subfamily K member 5 (KCNK5).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium channel subfamily K member 5 (KCNK5).	[20]

References

• [1] Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy.PLoS One. 2016 May 26;11(5):e0156456. doi: 10.1371/journal.pone.0156456. eCollection 2016.
• [2] Upregulation of K2P5.1 potassium channels in multiple sclerosis.Ann Neurol. 2010 Jul;68(1):58-69. doi: 10.1002/ana.22010.
• [3] The two-pore domain potassium channel KCNK5: induction by estrogen receptor alpha and role in proliferation of breast cancer cells.Mol Endocrinol. 2011 Aug;25(8):1326-36. doi: 10.1210/me.2011-0045. Epub 2011 Jun 16.
• [4] Task2 potassium channels set central respiratory CO2 and O2 sensitivity.Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2325-30. doi: 10.1073/pnas.0910059107. Epub 2010 Jan 19.
• [5] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [6] Identification and characterization of outcome measures reported in animal models of epilepsy: Protocol for a systematic review of the literature-A TASK2 report of the AES/ILAE Translational Task Force of the ILAE.Epilepsia. 2017 Nov;58 Suppl 4:68-77. doi: 10.1111/epi.13908.
• [7] 14-3-3 Proteins regulate K(2P) 5.1 surface expression on T lymphocytes.Traffic. 2017 Jan;18(1):29-43. doi: 10.1111/tra.12455. Epub 2016 Nov 27.
• [8] Mutations of the Twik-Related Acid-Sensitive K+ Channel 2 Promoter in Human Primary Aldosteronism.Endocrinology. 2018 Mar 1;159(3):1352-1359. doi: 10.1210/en.2017-03119.
• [9] Upregulated TWIK-related acid-sensitive K+ channel-2 in neurons and perivascular astrocytes in the hippocampus of experimental temporal lobe epilepsy.Epilepsia. 2009 Apr;50(4):654-63. doi: 10.1111/j.1528-1167.2008.01957.x. Epub 2009 Feb 12.
• [10] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [11] Fronto-parietal hypo-activation during working memory independent of structural abnormalities: conjoint fMRI and sMRI analyses in adolescent offspring of schizophrenia patients.Neuroimage. 2011 Sep 1;58(1):234-41. doi: 10.1016/j.neuroimage.2011.06.033. Epub 2011 Jun 29.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] 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.
• [14] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [15] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [16] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [17] 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.
• [18] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] 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.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.