Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHDD9F6)

• DOT Name: Potassium voltage-gated channel subfamily S member 3 (KCNS3)
• Synonyms: Delayed-rectifier K(+) channel alpha subunit 3; Voltage-gated potassium channel subunit Kv9.3
• Gene Name: KCNS3
• Related Disease:
  Schizophrenia
  Asthma
• UniProt ID: KCNS3_HUMAN
• Pfam ID: PF02214 ; PF00520
• Sequence:
  MVFGEFFHRPGQDEELVNLNVGGFKQSVDQSTLLRFPHTRLGKLLTCHSEEAILELCDDY
  SVADKEYYFDRNPSLFRYVLNFYYTGKLHVMEELCVFSFCQEIEYWGINELFIDSCCSNR
  YQERKEENHEKDWDQKSHDVSTDSSFEESSLFEKELEKFDTLRFGQLRKKIWIRMENPAY
  CLSAKLIAISSLSVVLASIVAMCVHSMSEFQNEDGEVDDPVLEGVEIACIAWFTGELAVR
  LAAAPCQKKFWKNPLNIIDFVSIIPFYATLAVDTKEEESEDIENMGKVVQILRLMRIFRI
  LKLARHSVGLRSLGATLRHSYHEVGLLLLFLSVGISIFSVLIYSVEKDDHTSSLTSIPIC
  WWWATISMTTVGYGDTHPVTLAGKLIASTCIICGILVVALPITIIFNKFSKYYQKQKDID
  VDQCSEDAPEKCHELPYFNIRDIYAQRMHTFITSLSSVGIVVSDPDSTDASSIEDNEDIC
  NTTSLENCTAK
• Function: Potassium channel subunit that does not form functional channels by itself. Can form functional heterotetrameric channels with KCNB1; modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1. Heterotetrameric channel activity formed with KCNB1 show increased current amplitude with the threshold for action potential activation shifted towards more negative values in hypoxic-treated pulmonary artery smooth muscle cells.
• Tissue Specificity: Detected in whole normal term placental and placental chorionic plate arteries and veins. Detected in syncytiotrophoblast and in blood vessel endothelium within intermediate villi and chorionic plate (at protein level) . Detected in most tissues, but not in peripheral blood lymphocytes. The highest levels of expression are in lung .
• Reactome Pathway:
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	moderate	Altered Expression	[1]
Asthma	DISW9QNS	Limited	Biomarker	[2]

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 S member 3 (KCNS3).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Potassium voltage-gated channel subfamily S member 3 (KCNS3).	[16]

References

• [1] Lower gene expression for KCNS3 potassium channel subunit in parvalbumin-containing neurons in the prefrontal cortex in schizophrenia.Am J Psychiatry. 2014 Jan;171(1):62-71. doi: 10.1176/appi.ajp.2013.13040468.
• [2] Single-nucleotide polymorphisms of the KCNS3 gene are significantly associated with airway hyperresponsiveness.Hum Genet. 2005 Apr;116(5):378-83. doi: 10.1007/s00439-005-1256-5. Epub 2005 Feb 16.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] 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.
• [8] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [13] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [15] 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.
• [16] 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.