Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMED202)

• DOT Name: Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5)
• Synonyms: KQT-like 5; Potassium channel subunit alpha KvLQT5; Voltage-gated potassium channel subunit Kv7.5
• Gene Name: KCNQ5
• Related Disease:
  Intellectual disability, autosomal dominant 46
  Autosomal dominant non-syndromic intellectual disability
• UniProt ID: KCNQ5_HUMAN
• PDB ID: 6B8Q
• Pfam ID: PF00520 ; PF03520
• Sequence:
  MPRHHAGGEEGGAAGLWVKSGAAAAAAGGGRLGSGMKDVESGRGRVLLNSAAARGDGLLL
  LGTRAATLGGGGGGLRESRRGKQGARMSLLGKPLSYTSSQSCRRNVKYRRVQNYLYNVLE
  RPRGWAFIYHAFVFLLVFGCLILSVFSTIPEHTKLASSCLLILEFVMIVVFGLEFIIRIW
  SAGCCCRYRGWQGRLRFARKPFCVIDTIVLIASIAVVSAKTQGNIFATSALRSLRFLQIL
  RMVRMDRRGGTWKLLGSVVYAHSKELITAWYIGFLVLIFSSFLVYLVEKDANKEFSTYAD
  ALWWGTITLTTIGYGDKTPLTWLGRLLSAGFALLGISFFALPAGILGSGFALKVQEQHRQ
  KHFEKRRNPAANLIQCVWRSYAADEKSVSIATWKPHLKALHTCSPTKKEQGEASSSQKLS
  FKERVRMASPRGQSIKSRQASVGDRRSPSTDITAEGSPTKVQKSWSFNDRTRFRPSLRLK
  SSQPKPVIDADTALGTDDVYDEKGCQCDVSVEDLTPPLKTVIRAIRIMKFHVAKRKFKET
  LRPYDVKDVIEQYSAGHLDMLCRIKSLQTRVDQILGKGQITSDKKSREKITAEHETTDDL
  SMLGRVVKVEKQVQSIESKLDCLLDIYQQVLRKGSASALALASFQIPPFECEQTSDYQSP
  VDSKDLSGSAQNSGCLSRSTSANISRGLQFILTPNEFSAQTFYALSPTMHSQATQVPISQ
  SDGSAVAATNTIANQINTAPKPAAPTTLQIPPPLPAIKHLPRPETLHPNPAGLQESISDV
  TTCLVASKENVQVAQSNLTKDRSMRKSFDMGGETLLSVCPMVPKDLGKSLSVQNLIRSTE
  ELNIQLSGSESSGSRGSQDFYPKWRESKLFITDEEVGPEETETDTFDAAPQPAREAAFAS
  DSLRTGRSRSSQSICKAGESTDALSLPHVKLK
• Function: Associates with KCNQ3 to form a potassium channel which contributes to M-type current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons. Therefore, it is important in the regulation of neuronal excitability. May contribute, with other potassium channels, to the molecular diversity of a heterogeneous population of M-channels, varying in kinetic and pharmacological properties, which underlie this physiologically important current. Insensitive to tetraethylammonium, but inhibited by barium, linopirdine and XE991. Activated by niflumic acid and the anticonvulsant retigabine. As the native M-channel, the potassium channel composed of KCNQ3 and KCNQ5 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1.
• Tissue Specificity: Strongly expressed in brain and skeletal muscle. In brain, expressed in cerebral cortex, occipital pole, frontal lobe and temporal lobe. Lower levels in hippocampus and putamen. Low to undetectable levels in medulla, cerebellum and thalamus.
• KEGG Pathway: Cholinergic sy.pse (hsa04725)
• Reactome Pathway: 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
Intellectual disability, autosomal dominant 46	DISAT096	Strong	Autosomal dominant	[1]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[1]

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 KQT member 5 (KCNQ5).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[4]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[10]
BENZOYLENUREA	DMY5O1U	Investigative	BENZOYLENUREA increases the activity of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily KQT member 5 (KCNQ5).	[7]

References

• [1] Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy. Am J Hum Genet. 2017 Jul 6;101(1):65-74. doi: 10.1016/j.ajhg.2017.05.016. Epub 2017 Jun 29.
• [2] 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.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] 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.
• [8] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] 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.