Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTIGYN7)

• DOT Name: Potassium voltage-gated channel subfamily A member 4 (KCNA4)
• Synonyms: HPCN2; Voltage-gated K(+) channel HuKII; Voltage-gated potassium channel HBK4; Voltage-gated potassium channel HK1; Voltage-gated potassium channel subunit Kv1.4
• Gene Name: KCNA4
• Related Disease:
  Drug-resistant tuberculosis
  Familial long QT syndrome
  Long QT syndrome 1
  Long QT syndrome
  Ventricular fibrillation
  Arrhythmia
  Microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum
  Osteoarthritis
  Rheumatoid arthritis
• UniProt ID: KCNA4_HUMAN
• Pfam ID: PF02214 ; PF00520 ; PF07941
• Sequence:
  MEVAMVSAESSGCNSHMPYGYAAQARARERERLAHSRAAAAAAVAAATAAVEGSGGSGGG
  SHHHHQSRGACTSHDPQSSRGSRRRRRQRSEKKKAHYRQSSFPHCSDLMPSGSEEKILRE
  LSEEEEDEEEEEEEEEEGRFYYSEDDHGDECSYTDLLPQDEGGGGYSSVRYSDCCERVVI
  NVSGLRFETQMKTLAQFPETLLGDPEKRTQYFDPLRNEYFFDRNRPSFDAILYYYQSGGR
  LKRPVNVPFDIFTEEVKFYQLGEEALLKFREDEGFVREEEDRALPENEFKKQIWLLFEYP
  ESSSPARGIAIVSVLVILISIVIFCLETLPEFRDDRDLVMALSAGGHGGLLNDTSAPHLE
  NSGHTIFNDPFFIVETVCIVWFSFEFVVRCFACPSQALFFKNIMNIIDIVSILPYFITLG
  TDLAQQQGGGNGQQQQAMSFAILRIIRLVRVFRIFKLSRHSKGLQILGHTLRASMRELGL
  LIFFLFIGVILFSSAVYFAEADEPTTHFQSIPDAFWWAVVTMTTVGYGDMKPITVGGKIV
  GSLCAIAGVLTIALPVPVIVSNFNYFYHRETENEEQTQLTQNAVSCPYLPSNLLKKFRSS
  TSSSLGDKSEYLEMEEGVKESLCAKEEKCQGKGDDSETDKNNCSNAKAVETDV
• Function: Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient. The channel alternates between opened and closed conformations in response to the voltage difference across the membrane. Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members as well; channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes, making it difficult to assign currents observed in intact tissues to any particular potassium channel family member. Homotetrameric KCNA4 forms a potassium channel that opens in response to membrane depolarization, followed by rapid spontaneous channel closure. Likewise, a heterotetrameric channel formed by KCNA1 and KCNA4 shows rapid inactivation.
• Tissue Specificity: Expressed in brain, and at lower levels in the testis, lung, kidney, colon and heart . Detected in heart ventricle.
• KEGG Pathway:
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Drug-resistant tuberculosis	DIS5BUFB	Strong	Genetic Variation	[1]
Familial long QT syndrome	DISRNNCY	Strong	Biomarker	[2]
Long QT syndrome 1	DISXK5OU	Strong	Genetic Variation	[3]
Long QT syndrome	DISMKWS3	moderate	Genetic Variation	[4]
Ventricular fibrillation	DIS7IN76	moderate	Biomarker	[5]
Arrhythmia	DISFF2NI	Limited	Biomarker	[6]
Microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum	DISDVWDI	Limited	Autosomal recessive	[7]
Osteoarthritis	DIS05URM	Limited	Altered Expression	[8]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[8]

4 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 A member 4 (KCNA4).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Potassium voltage-gated channel subfamily A member 4 (KCNA4).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Potassium voltage-gated channel subfamily A member 4 (KCNA4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Potassium voltage-gated channel subfamily A member 4 (KCNA4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium voltage-gated channel subfamily A member 4 (KCNA4).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Potassium voltage-gated channel subfamily A member 4 (KCNA4).	[12]

References

• [1] 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel.Bioorg Med Chem. 2019 Apr 1;27(7):1292-1307. doi: 10.1016/j.bmc.2019.02.026. Epub 2019 Feb 15.
• [2] Drug-induced torsades de pointes: the evolving role of pharmacogenetics.Heart Rhythm. 2005 Nov;2(2 Suppl):S30-7. doi: 10.1016/j.hrthm.2005.08.007.
• [3] A recessive variant of the Romano-Ward long-QT syndrome?.Circulation. 1998 Jun 23;97(24):2420-5. doi: 10.1161/01.cir.97.24.2420.
• [4] Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene.Circulation. 2007 May 15;115(19):2481-9. doi: 10.1161/CIRCULATIONAHA.106.665406. Epub 2007 Apr 30.
• [5] Mutation in KCNE1 associated to early repolarization syndrome by modulation of slowly activating delayed rectifier K(+) current.Exp Cell Res. 2018 Feb 15;363(2):315-320. doi: 10.1016/j.yexcr.2018.01.030. Epub 2018 Feb 1.
• [6] Development of models for predicting Torsade de Pointes cardiac arrhythmias using perceptron neural networks.BMC Bioinformatics. 2017 Dec 28;18(Suppl 14):497. doi: 10.1186/s12859-017-1895-2.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] Inhibition of hexokinases holds potential as treatment strategy for rheumatoid arthritis.Arthritis Res Ther. 2019 Apr 3;21(1):87. doi: 10.1186/s13075-019-1865-3.
• [9] 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.
• [10] 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.
• [11] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [12] 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.
• [13] 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.
• [14] 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.