Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNYW0OL)

• DOT Name: Potassium voltage-gated channel subfamily E member 4 (KCNE4)
• Synonyms: MinK-related peptide 3; Minimum potassium ion channel-related peptide 3; Potassium channel subunit beta MiRP3
• Gene Name: KCNE4
• Related Disease:
  Narcolepsy
  Atrial fibrillation
  Asthma
  Arrhythmia
  Neoplasm
• UniProt ID: KCNE4_HUMAN
• Pfam ID: PF02060
• Sequence:
  MHFLTIYPNCSSGVVRAQSRTEQKNPLGLDDLGIQNLGQTVSLAPAVEAASMLKMEPLNS
  THPGTAASSSPLESRAAGGGSGNGNEYFYILVVMSFYGIFLIGIMLGYMKSKRREKKSSL
  LLLYKDEERLWGEAMKPLPVVSGLRSVQVPLMLNMLQESVAPALSCTLCSMEGDSVSSES
  SSPDVHLTIQEEGADDELEETSETPLNESSEGSSENIHQNS
• Function: Ancillary protein that assembles as a beta subunit with a voltage-gated potassium channel complex of pore-forming alpha subunits. Modulates the gating kinetics and enhances stability of the channel complex. Associates with KCNQ1/KVLTQ1 and inhibits potassium currents; [Isoform 2]: May inhibit KCNQ4-mediated potassium currents.
• Tissue Specificity: Predominantly expressed in embryo and adult uterus. Low expression found in kidney, small intestine, lung and heart.; [Isoform 1]: Detected in kidney, thymus, and uterus (at protein level).
• Reactome Pathway:
  Phase 2 - plateau phase (R-HSA-5576893)
  Phase 3 - rapid repolarisation (R-HSA-5576890)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[2]
Asthma	DISW9QNS	moderate	Genetic Variation	[3]
Arrhythmia	DISFF2NI	Limited	Biomarker	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]

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 Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Potassium voltage-gated channel subfamily E member 4 (KCNE4).	[15]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Deep sequencing of atrial fibrillation patients with mitral valve regurgitation shows no evidence of mosaicism but reveals novel rare germline variants.Heart Rhythm. 2017 Oct;14(10):1531-1538. doi: 10.1016/j.hrthm.2017.05.027. Epub 2017 May 24.
• [3] [Genome-wide association study of allergic diseases in Russians of Western Siberia].Mol Biol (Mosk). 2011 May-Jun;45(3):464-72.
• [4] Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice.Sci Rep. 2018 May 29;8(1):8258. doi: 10.1038/s41598-018-26599-8.
• [5] Ion channels expression and function are strongly modified in solid tumors and vascular malformations.J Transl Med. 2016 Oct 4;14(1):285. doi: 10.1186/s12967-016-1038-y.
• [6] 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.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [9] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] 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.
• [12] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] 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.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.