Details of Drug Off-Target (DOT)

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

• DOT Name: Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3)
• Synonyms: KQT-like 3; Potassium channel subunit alpha KvLQT3; Voltage-gated potassium channel subunit Kv7.3
• Gene Name: KCNQ3
• Related Disease:
  Seizures, benign familial neonatal, 2
  Benign familial infantile epilepsy
  Benign neonatal seizures
• UniProt ID: KCNQ3_HUMAN
• PDB ID: 5J03
• Pfam ID: PF00520 ; PF03520 ; PF11956
• Sequence:
  MGLKARRAAGAAGGGGDGGGGGGGAANPAGGDAAAAGDEERKVGLAPGDVEQVTLALGAG
  ADKDGTLLLEGGGRDEGQRRTPQGIGLLAKTPLSRPVKRNNAKYRRIQTLIYDALERPRG
  WALLYHALVFLIVLGCLILAVLTTFKEYETVSGDWLLLLETFAIFIFGAEFALRIWAAGC
  CCRYKGWRGRLKFARKPLCMLDIFVLIASVPVVAVGNQGNVLATSLRSLRFLQILRMLRM
  DRRGGTWKLLGSAICAHSKELITAWYIGFLTLILSSFLVYLVEKDVPEVDAQGEEMKEEF
  ETYADALWWGLITLATIGYGDKTPKTWEGRLIAATFSLIGVSFFALPAGILGSGLALKVQ
  EQHRQKHFEKRRKPAAELIQAAWRYYATNPNRIDLVATWRFYESVVSFPFFRKEQLEAAS
  SQKLGLLDRVRLSNPRGSNTKGKLFTPLNVDAIEESPSKEPKPVGLNNKERFRTAFRMKA
  YAFWQSSEDAGTGDPMAEDRGYGNDFPIEDMIPTLKAAIRAVRILQFRLYKKKFKETLRP
  YDVKDVIEQYSAGHLDMLSRIKYLQTRIDMIFTPGPPSTPKHKKSQKGSAFTFPSQQSPR
  NEPYVARPSTSEIEDQSMMGKFVKVERQVQDMGKKLDFLVDMHMQHMERLQVQVTEYYPT
  KGTSSPAEAEKKEDNRYSDLKTIICNYSETGPPEPPYSFHQVTIDKVSPYGFFAHDPVNL
  PRGGPSSGKVQATPPSSATTYVERPTVLPILTLLDSRVSCHSQADLQGPYSDRISPRQRR
  SITRDSDTPLSLMSVNHEELERSPSGFSISQDRDDYVFGPNGGSSWMREKRYLAEGETDT
  DTDPFTPSGSMPLSSTGDGISDSVWTPSNKPI
• Function: Associates with KCNQ2 or KCNQ5 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. Therefore, it is important in the regulation of neuronal excitability. KCNQ2-KCNQ3 channel is selectively permeable to other cations besides potassium, in decreasing order of affinity K(+) > Rb(+) > Cs(+) > Na(+). Associates with Na(+)-coupled myo-inositol symporter SLC5A3 forming a coregulatory complex that alters ion selectivity, increasing Na(+) and Cs(+) permeation relative to K(+) permeation.
• Tissue Specificity: Predominantly expressed in brain.
• KEGG Pathway: Cholinergic sy.pse (hsa04725)
• Reactome Pathway:
  Interaction between L1 and Ankyrins (R-HSA-445095)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Seizures, benign familial neonatal, 2	DISLZ3VQ	Strong	Autosomal dominant	[1]
Benign familial infantile epilepsy	DISFYXOW	Supportive	Autosomal dominant	[2]
Benign neonatal seizures	DISWNBHF	Supportive	Autosomal dominant	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Retigabine	DMGNYIH	Approved	Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3) decreases the response to substance of Retigabine.	[14]

7 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 KQT member 3 (KCNQ3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[12]
BENZOYLENUREA	DMY5O1U	Investigative	BENZOYLENUREA increases the activity of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily KQT member 3 (KCNQ3).	[9]

References

• [1] Altered KCNQ3 potassium channel function caused by the W309R pore-helix mutation found in human epilepsy. J Membr Biol. 2008 Mar;222(2):55-63. doi: 10.1007/s00232-008-9097-5. Epub 2008 Apr 20.
• [2] Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia. 2013 Mar;54(3):425-36. doi: 10.1111/epi.12089. Epub 2013 Jan 29.
• [3] KCNQ3-Related Disorders. 2014 May 22 [updated 2023 Sep 28]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [4] 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.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] 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.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] 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.
• [13] KCNQ2/3 openers show differential selectivity and site of action across multiple KCNQ channels. J Neurosci Methods. 2011 Aug 30;200(1):54-62. doi: 10.1016/j.jneumeth.2011.06.014. Epub 2011 Jun 23.
• [14] The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine. J Biol Chem. 2016 Feb 5;291(6):2931-7. doi: 10.1074/jbc.M115.683185. Epub 2015 Dec 1.