Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8SPJNX)

• DOT Name: Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1)
• Synonyms: IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1; KQT-like 1; Voltage-gated potassium channel subunit Kv7.1
• Gene Name: KCNQ1
• Related Disease:
  Jervell and Lange-Nielsen syndrome
  Jervell and Lange-Nielsen syndrome 1
  Long QT syndrome
  Long QT syndrome 1
  Atrial fibrillation, familial, 3
  Short QT syndrome
  Short QT syndrome type 2
  Familial atrial fibrillation
  Obsolete Jervell and Lange-Nielsen syndrome
  Hypertrophic cardiomyopathy
• UniProt ID: KCNQ1_HUMAN
• PDB ID: 3BJ4; 3HFC; 3HFE; 4UMO; 4V0C; 6MIE; 6UZZ; 6V00; 6V01; 7VUO; 7VVD; 7VVH; 7XNI; 7XNK; 7XNL; 7XNN; 8SIK; 8SIM; 8SIN
• Pfam ID: PF00520 ; PF03520
• Sequence:
  MAAASSPPRAERKRWGWGRLPGARRGSAGLAKKCPFSLELAEGGPAGGALYAPIAPGAPG
  PAPPASPAAPAAPPVASDLGPRPPVSLDPRVSIYSTRRPVLARTHVQGRVYNFLERPTGW
  KCFVYHFAVFLIVLVCLIFSVLSTIEQYAALATGTLFWMEIVLVVFFGTEYVVRLWSAGC
  RSKYVGLWGRLRFARKPISIIDLIVVVASMVVLCVGSKGQVFATSAIRGIRFLQILRMLH
  VDRQGGTWRLLGSVVFIHRQELITTLYIGFLGLIFSSYFVYLAEKDAVNESGRVEFGSYA
  DALWWGVVTVTTIGYGDKVPQTWVGKTIASCFSVFAISFFALPAGILGSGFALKVQQKQR
  QKHFNRQIPAAASLIQTAWRCYAAENPDSSTWKIYIRKAPRSHTLLSPSPKPKKSVVVKK
  KKFKLDKDNGVTPGEKMLTVPHITCDPPEERRLDHFSVDGYDSSVRKSPTLLEVSMPHFM
  RTNSFAEDLDLEGETLLTPITHISQLREHHRATIKVIRRMQYFVAKKKFQQARKPYDVRD
  VIEQYSQGHLNLMVRIKELQRRLDQSIGKPSLFISVSEKSKDRGSNTIGARLNRVEDKVT
  QLDQRLALITDMLHQLLSLHGGSTPGSGGPPREGGAHITQPCGSGGSVDPELFLPSNTLP
  TYEQLTVPRRGPDEGS
• Function: Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon. Associates with KCNE beta subunits that modulates current kinetics. Induces a voltage-dependent current by rapidly activating and slowly deactivating potassium-selective outward current. Promotes also a delayed voltage activated potassium current showing outward rectification characteristic. During beta-adrenergic receptor stimulation participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks). Muscarinic agonist oxotremorine-M strongly suppresses KCNQ1/KCNE1 current. When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions. This interaction with KCNE3 is reduced by 17beta-estradiol, resulting in the reduction of currents. During conditions of increased substrate load, maintains the driving force for proximal tubular and intestinal sodium ions absorption, gastric acid secretion, and cAMP-induced jejunal chloride ions secretion. Allows the provision of potassium ions to the luminal membrane of the secretory canaliculus in the resting state as well as during stimulated acid secretion. When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current. When associated with KCNE4, inhibits voltage-gated potassium channel activity. When associated with KCNE5, this complex only conducts current upon strong and continued depolarization. Also forms a heterotetramer with KCNQ5; has a voltage-gated potassium channel activity. Binds with phosphatidylinositol 4,5-bisphosphate. KCNQ1-KCNE2 channel associates with Na(+)-coupled myo-inositol symporter in the apical membrane of choroid plexus epithelium and regulates the myo-inositol gradient between blood and cerebrospinal fluid with an impact on neuron excitability; [Isoform 2]: Non-functional alone but modulatory when coexpressed with the full-length isoform 1.
• Tissue Specificity: Abundantly expressed in heart, pancreas, prostate, kidney, small intestine and peripheral blood leukocytes. Less abundant in placenta, lung, spleen, colon, thymus, testis and ovaries.
• KEGG Pathway:
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Cholinergic sy.pse (hsa04725)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Protein digestion and absorption (hsa04974)
  Vibrio cholerae infection (hsa05110)
• Reactome Pathway:
  Phase 3 - rapid repolarisation (R-HSA-5576890)
  Phase 2 - plateau phase (R-HSA-5576893)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Jervell and Lange-Nielsen syndrome	DISGCX89	Definitive	Autosomal recessive	[1]
Jervell and Lange-Nielsen syndrome 1	DISVWU3A	Definitive	Autosomal recessive	[2]
Long QT syndrome	DISMKWS3	Definitive	Autosomal dominant	[1]
Long QT syndrome 1	DISXK5OU	Definitive	Autosomal dominant	[3]
Atrial fibrillation, familial, 3	DISCVLOG	Strong	Autosomal dominant	[4]
Short QT syndrome	DISOI9X1	Strong	Autosomal dominant	[1]
Short QT syndrome type 2	DISHGLMM	Strong	Autosomal dominant	[5]
Familial atrial fibrillation	DISL4AGF	Supportive	Autosomal dominant	[6]
Obsolete Jervell and Lange-Nielsen syndrome	DISRHOUU	Supportive	Autosomal recessive	[7]
Hypertrophic cardiomyopathy	DISQG2AI	Disputed	Autosomal dominant	[1]

This DOT Affected the Drug Response of 19 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Propranolol	DM79NTF	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) affects the response to substance of Propranolol.	[21]
Erythromycin	DM4K7GQ	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Torsade de pointes ADR of Erythromycin.	[22]
Atenolol	DMNKG1Z	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) affects the response to substance of Atenolol.	[21]
Quinidine	DMLPICK	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Torsade de pointes ADR of Quinidine.	[22]
Flecainide	DMSQDLE	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Flecainide.	[22]
Clarithromycin	DM4M1SG	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Torsade de pointes ADR of Clarithromycin.	[22]
Hydrochlorothiazide	DMUSZHD	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Hydrochlorothiazide.	[22]
Procainamide	DMNMXR8	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Procainamide.	[22]
Disopyramide	DM5SYZP	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Disopyramide.	[22]
Cisapride	DMY7PED	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Torsade de pointes ADR of Cisapride.	[22]
Diltiazem	DMAI7ZV	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Diltiazem.	[22]
Sotalol	DML60TN	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Sotalol.	[22]
Propafenone	DMPIBJK	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Propafenone.	[22]
Dofetilide	DMPN1TW	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Dofetilide.	[22]
Tocainide	DMYNMDP	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Tocainide.	[22]
Aprindine	DMBXWU8	Approved	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) affects the response to substance of Aprindine.	[21]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Amiodarone.	[22]
Verapamil	DMA7PEW	Phase 2/3 Trial	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the Sudden cardiac death ADR of Verapamil.	[22]
Terfenadine	DM4KLPT	Withdrawn from market	Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) increases the response to substance of Terfenadine.	[14]

4 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 KQT member 1 (KCNQ1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[11]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[13]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[10]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[10]
Ropivacaine	DMSPJG2	Approved	Ropivacaine decreases the activity of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[14]
Bupivacaine	DM4PRFC	Approved	Bupivacaine decreases the activity of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[14]
Mepivacaine	DMH2NMY	Approved	Mepivacaine decreases the activity of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[17]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[19]
(3R,4S)-293B	DM47BEG	Investigative	(3R,4S)-293B decreases the activity of Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1).	[20]

References

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