Details of Drug Off-Target (DOT)

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

• DOT Name: Potassium channel subfamily K member 1 (KCNK1)
• Synonyms: Inward rectifying potassium channel protein TWIK-1; Potassium channel K2P1; Potassium channel KCNO1
• Gene Name: KCNK1
• Related Disease:
  Glioma
  Heart valve disorder
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Matthew-Wood syndrome
  Hyperplasia
  Brugada syndrome
  Chronic obstructive pulmonary disease
• UniProt ID: KCNK1_HUMAN
• PDB ID: 3UKM
• Pfam ID: PF07885
• Sequence:
  MLQSLAGSSCVRLVERHRSAWCFGFLVLGYLLYLVFGAVVFSSVELPYEDLLRQELRKLK
  RRFLEEHECLSEQQLEQFLGRVLEASNYGVSVLSNASGNWNWDFTSALFFASTVLSTTGY
  GHTVPLSDGGKAFCIIYSVIGIPFTLLFLTAVVQRITVHVTRRPVLYFHIRWGFSKQVVA
  IVHAVLLGFVTVSCFFFIPAAVFSVLEDDWNFLESFYFCFISLSTIGLGDYVPGEGYNQK
  FRELYKIGITCYLLLGLIAMLVVLETFCELHELKKFRKMFYVKKDKDEDQVHIIEHDQLS
  FSSITDQAAGMKEDQKQNEPFVATQSSACVDGPANH
• Function: Ion channel that contributes to passive transmembrane potassium transport and to the regulation of the resting membrane potential in brain astrocytes, but also in kidney and in other tissues. Forms dimeric channels through which potassium ions pass in accordance with their electrochemical gradient. The channel is selective for K(+) ions at physiological potassium concentrations and at neutral pH, but becomes permeable to Na(+) at subphysiological K(+) levels and upon acidification of the extracellular medium. The homodimer has very low potassium channel activity, when expressed in heterologous systems, and can function as weakly inward rectifying potassium channel. Channel activity is modulated by activation of serotonin receptors. Heterodimeric channels containing KCNK1 and KCNK2 have much higher activity, and may represent the predominant form in astrocytes. Heterodimeric channels containing KCNK1 and KCNK3 or KCNK9 have much higher activity. Heterodimeric channels formed by KCNK1 and KCNK9 may contribute to halothane-sensitive currents. Mediates outward rectifying potassium currents in dentate gyrus granule cells and contributes to the regulation of their resting membrane potential. Contributes to the regulation of action potential firing in dentate gyrus granule cells and down-regulates their intrinsic excitability. In astrocytes, the heterodimer formed by KCNK1 and KCNK2 is required for rapid glutamate release in response to activation of G-protein coupled receptors, such as F2R and CNR1. Required for normal ion and water transport in the kidney. Contributes to the regulation of the resting membrane potential of pancreatic beta cells. The low channel activity of homodimeric KCNK1 may be due to sumoylation. The low channel activity may be due to rapid internalization from the cell membrane and retention in recycling endosomes.
• Tissue Specificity: Detected in bronchial epithelial cells . Detected in heart left atrium and left ventricle . Detected in cardiac myocytes (at protein level) . Widely expressed with high levels in heart, brain and kidney, and lower levels in colon, ovary, placenta, lung and liver . Highly expressed in cerebellum, and detected at lower levels in amygdala, caudate nucleus, brain cortex, hippocampus, putamen, substantia nigra, thalamus, dorsal root ganglion, spinal cord, pituitary, heart, kidney, lung, placenta, pancreas, stomach, small intestine, uterus and prostate . Detected in right and left heart ventricle and atrium, and in heart Purkinje fibers .
• Reactome Pathway:
  Phase 4 - resting membrane potential (R-HSA-5576886)
  Tandem of pore domain in a weak inwardly rectifying K+ channels (TWIK) (R-HSA-1299308)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Altered Expression	[1]
Heart valve disorder	DIS84O7T	Definitive	Altered Expression	[2]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[5]
Hyperplasia	DISK4DFB	moderate	Therapeutic	[6]
Brugada syndrome	DISSGN0E	Limited	Altered Expression	[7]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Potassium channel subfamily K member 1 (KCNK1) affects the response to substance of Cisplatin.	[24]
Methotrexate	DM2TEOL	Approved	Potassium channel subfamily K member 1 (KCNK1) affects the response to substance of Methotrexate.	[24]

15 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 1 (KCNK1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Potassium channel subfamily K member 1 (KCNK1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Potassium channel subfamily K member 1 (KCNK1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Potassium channel subfamily K member 1 (KCNK1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Potassium channel subfamily K member 1 (KCNK1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Potassium channel subfamily K member 1 (KCNK1).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Potassium channel subfamily K member 1 (KCNK1).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Potassium channel subfamily K member 1 (KCNK1).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Potassium channel subfamily K member 1 (KCNK1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Potassium channel subfamily K member 1 (KCNK1).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Potassium channel subfamily K member 1 (KCNK1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Potassium channel subfamily K member 1 (KCNK1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Potassium channel subfamily K member 1 (KCNK1).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Potassium channel subfamily K member 1 (KCNK1).	[22]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Potassium channel subfamily K member 1 (KCNK1).	[23]

References

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• [3] The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size.J Mol Cell Cardiol. 2016 Aug;97:24-35. doi: 10.1016/j.yjmcc.2016.04.006. Epub 2016 Apr 19.
• [4] Fertility concerns, preservation strategies and quality of life in young women with breast cancer: Baseline results from an ongoing prospective cohort study in selected European Centers.Breast. 2019 Oct;47:85-92. doi: 10.1016/j.breast.2019.07.001. Epub 2019 Jul 10.
• [5] 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.
• [6] Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia.Toxicol Sci. 2013 Mar;132(1):151-61. doi: 10.1093/toxsci/kfs338. Epub 2013 Jan 4.
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• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] 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.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] 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.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [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] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [23] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.