Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXSP3AA)

• DOT Name: Potassium voltage-gated channel subfamily A member 3 (KCNA3)
• Synonyms: HGK5; HLK3; HPCN3; Voltage-gated K(+) channel HuKIII; Voltage-gated potassium channel subunit Kv1.3
• Gene Name: KCNA3
• UniProt ID: KCNA3_HUMAN
• PDB ID: 4BGC; 7EJ1; 7EJ2; 7SSV; 7SSX; 7SSY; 7SSZ; 8DFL
• Pfam ID: PF02214 ; PF00520
• Sequence:
  MDERLSLLRSPPPPSARHRAHPPQRPASSGGAHTLVNHGYAEPAAGRELPPDMTVVPGDH
  LLEPEVADGGGAPPQGGCGGGGCDRYEPLPPSLPAAGEQDCCGERVVINISGLRFETQLK
  TLCQFPETLLGDPKRRMRYFDPLRNEYFFDRNRPSFDAILYYYQSGGRIRRPVNVPIDIF
  SEEIRFYQLGEEAMEKFREDEGFLREEERPLPRRDFQRQVWLLFEYPESSGPARGIAIVS
  VLVILISIVIFCLETLPEFRDEKDYPASTSQDSFEAAGNSTSGSRAGASSFSDPFFVVET
  LCIIWFSFELLVRFFACPSKATFSRNIMNLIDIVAIIPYFITLGTELAERQGNGQQAMSL
  AILRVIRLVRVFRIFKLSRHSKGLQILGQTLKASMRELGLLIFFLFIGVILFSSAVYFAE
  ADDPTSGFSSIPDAFWWAVVTMTTVGYGDMHPVTIGGKIVGSLCAIAGVLTIALPVPVIV
  SNFNYFYHRETEGEEQSQYMHVGSCQHLSSSAEELRKARSNSTLSKSEYMVIEEGGMNHS
  AFPQTPFKTGNSTATCTTNNNPNSCVNIKKIFTDV
• Function: Mediates the voltage-dependent potassium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a potassium-selective channel through which potassium ions may pass in accordance with their electrochemical gradient.
• Reactome Pathway: Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluoxetine	DM3PD2C	Approved	Fluoxetine decreases the activity of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[3]
Nifedipine	DMSVOZT	Approved	Nifedipine decreases the activity of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[3]
Reserpine	DM6VM38	Approved	Reserpine decreases the activity of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[4]
Econazole	DMFSWGH	Approved	Econazole decreases the activity of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[4]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil decreases the activity of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[6]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Potassium voltage-gated channel subfamily A member 3 (KCNA3).	[7]

References

• [1] 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.
• [2] 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.
• [3] A cell-based Rb(+)-flux assay of the Kv1.3 potassium channel. Assay Drug Dev Technol. 2007 Jun;5(3):373-80. doi: 10.1089/adt.2006.004.
• [4] Identification of quaternary ammonium compounds as potent inhibitors of hERG potassium channels. Toxicol Appl Pharmacol. 2011 May 1;252(3):250-8. doi: 10.1016/j.taap.2011.02.016. Epub 2011 Feb 26.
• [5] 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.
• [6] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [7] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.