Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKWKR91)

• DOT Name: Potassium voltage-gated channel subfamily E member 3 (KCNE3)
• Synonyms: MinK-related peptide 2; Minimum potassium ion channel-related peptide 2; Potassium channel subunit beta MiRP2
• Gene Name: KCNE3
• Related Disease:
  Alzheimer disease
  Arrhythmia
  Familial periodic paralysis
  Hyperkalemic periodic paralysis
  Hypokalemic periodic paralysis
  Hypokalemic periodic paralysis, type 1
  Long QT syndrome
  Meniere disease
  Brugada syndrome
  Brugada syndrome 6
  Atrial fibrillation
  Neoplasm
  Paramyotonia congenita of Von Eulenburg
• UniProt ID: KCNE3_HUMAN
• PDB ID: 2NDJ; 6V00; 6V01
• Pfam ID: PF02060
• Sequence:
  METTNGTETWYESLHAVLKALNATLHSNLLCRPGPGLGPDNQTEERRASLPGRDDNSYMY
  ILFVMFLFAVTVGSLILGYTRSRKVDKRSDPYHVYIKNRVSMI
• 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. Assembled with KCNB1 modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1. Associated with KCNC4/Kv3.4 is proposed to form the subthreshold voltage-gated potassium channel in skeletal muscle and to establish the resting membrane potential (RMP) in muscle cells. Associated with KCNQ1/KCLQT1 may form the intestinal cAMP-stimulated potassium channel involved in chloride secretion that produces a current with nearly instantaneous activation with a linear current-voltage relationship.
• Tissue Specificity: Expressed in hippocampal neurons (at protein level) . Widely expressed with highest levels in kidney and moderate levels in small intestine.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Phase 2 - plateau phase (R-HSA-5576893)
  Phase 3 - rapid repolarisation (R-HSA-5576890)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Arrhythmia	DISFF2NI	Strong	Genetic Variation	[2]
Familial periodic paralysis	DISD9YAA	Strong	Biomarker	[3]
Hyperkalemic periodic paralysis	DIS21WOL	Strong	Genetic Variation	[4]
Hypokalemic periodic paralysis	DISVIXI1	Strong	Genetic Variation	[5]
Hypokalemic periodic paralysis, type 1	DIS5GF2M	Strong	Genetic Variation	[6]
Long QT syndrome	DISMKWS3	moderate	Biomarker	[7]
Meniere disease	DISC5R5F	moderate	Biomarker	[8]
Brugada syndrome	DISSGN0E	Disputed	Autosomal dominant	[9]
Brugada syndrome 6	DISGHF9C	Disputed	Unknown	[10]
Atrial fibrillation	DIS15W6U	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Altered Expression	[12]
Paramyotonia congenita of Von Eulenburg	DISXYDU9	Limited	Biomarker	[13]

9 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 voltage-gated channel subfamily E member 3 (KCNE3).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[17]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[23]

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 voltage-gated channel subfamily E member 3 (KCNE3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Potassium voltage-gated channel subfamily E member 3 (KCNE3).	[24]

References

• [1] The MiRP2-Kv3.4 potassium channel: muscling in on Alzheimer's disease.Mol Pharmacol. 2007 Sep;72(3):499-501. doi: 10.1124/mol.107.039206. Epub 2007 Jun 26.
• [2] KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation.Gene. 2016 Jan 15;576(1 Pt 1):1-13. doi: 10.1016/j.gene.2015.09.059. Epub 2015 Sep 26.
• [3] Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis.FASEB J. 2006 Feb;20(2):293-301. doi: 10.1096/fj.05-5070com.
• [4] Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis.Neurotherapeutics. 2007 Apr;4(2):216-24. doi: 10.1016/j.nurt.2007.02.001.
• [5] Strict bed rest following lumbar puncture in children and adolescents is of no benefit.Neurology. 2004 Mar 23;62(6):1003-5. doi: 10.1212/01.wnl.0000115387.67958.0f.
• [6] A mutation in the KCNE3 potassium channel gene is associated with susceptibility to thyrotoxic hypokalemic periodic paralysis.J Clin Endocrinol Metab. 2002 Nov;87(11):4881-4. doi: 10.1210/jc.2002-020698.
• [7] Novel KCNE3 mutation reduces repolarizing potassium current and associated with long QT syndrome.Hum Mutat. 2009 Apr;30(4):557-63. doi: 10.1002/humu.20834.
• [8] Polymorphisms in KCNE1 or KCNE3 are not associated with Mnire disease in the Caucasian population.Am J Med Genet A. 2010 Jan;152A(1):67-74. doi: 10.1002/ajmg.a.33114.
• [9] 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.
• [10] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [11] Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation.Biomark Med. 2014;8(4):557-70. doi: 10.2217/bmm.13.137.
• [12] 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.
• [13] Sodium channel mutations in paramyotonia congenita and hyperkalemic periodic paralysis.Ann Neurol. 1993 Mar;33(3):300-7. doi: 10.1002/ana.410330312.
• [14] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [17] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.