Details of the Drug Transporter (DTP)

General Information of Drug Transporter (DTP) (ID: DTYE3RN)

• DTP Name: Voltage-gated potassium channel Kv7.1 (KCNQ1)
• Gene Name: KCNQ1
• UniProt ID: P51787 (KCNQ1_HUMAN)
• VARIDT ID: DTD0513
• Synonyms: ATFB1; ATFB3; IKs producing slow voltage-gated potassium channel subunit alpha KvLQT1; JLNS1; KCNA8; KCNA9; KCNQ1; KQT-like 1; KVLQT1; Kv1.9; Kv7.1; LQT; LQT1; RWS; SQT2; Potassium voltage-gated channel subfamily KQT member 1; WRS; Voltage-gated potassium channel subunit Kv7.1
• DTP Family: Voltage-Gated Ion Channel (VIC) Superfamily
• Tissue Specificity: Abundantly expressed in heart, pancreas,prostate, kidney, small intestine and peripheral blood leukocytes.Less abundant in placenta, lung, spleen, colon, thymus, testis andovaries.
• Sequence:
  MAAASSPPRAERKRWGWGRLPGARRGSAGLAKKCPFSLELAEGGPAGGALYAPIAPGAPG
  PAPPASPAAPAAPPVASDLGPRPPVSLDPRVSIYSTRRPVLARTHVQGRVYNFLERPTGW
  KCFVYHFAVFLIVLVCLIFSVLSTIEQYAALATGTLFWMEIVLVVFFGTEYVVRLWSAGC
  RSKYVGLWGRLRFARKPISIIDLIVVVASMVVLCVGSKGQVFATSAIRGIRFLQILRMLH
  VDRQGGTWRLLGSVVFIHRQELITTLYIGFLGLIFSSYFVYLAEKDAVNESGRVEFGSYA
  DALWWGVVTVTTIGYGDKVPQTWVGKTIASCFSVFAISFFALPAGILGSGFALKVQQKQR
  QKHFNRQIPAAASLIQTAWRCYAAENPDSSTWKIYIRKAPRSHTLLSPSPKPKKSVVVKK
  KKFKLDKDNGVTPGEKMLTVPHITCDPPEERRLDHFSVDGYDSSVRKSPTLLEVSMPHFM
  RTNSFAEDLDLEGETLLTPITHISQLREHHRATIKVIRRMQYFVAKKKFQQARKPYDVRD
  VIEQYSQGHLNLMVRIKELQRRLDQSIGKPSLFISVSEKSKDRGSNTIGARLNRVEDKVT
  QLDQRLALITDMLHQLLSLHGGSTPGSGGPPREGGAHITQPCGSGGSVDPELFLPSNTLP
  TYEQLTVPRRGPDEGS
• Function: This potassium transporter associates with KCNE beta subunits and Induces a voltage-dependent 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.
• Endogenous Substrate(s): Potassium ions
• TCDB ID: 1.A.1.15.6
• Gene ID: 3784
• KEGG Pathway:
  Adrenergic signaling in cardiomyocytes (hsa04261)
  Cholinergic synapse (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)

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Voltage-gated potassium channel Kv7.1 (KCNQ1) DTT Info
• DTP DTT Type: Successful

1 Approved Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Indapamide	DMGN1PW	Edema	MG29	Approved	[1]

1 Discontinued Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-768673	DMZ402C	N. A.	N. A.	Terminated	[2]

13 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(3R,4S)-293B	DM47BEG	Discovery agent	N.A.	Investigative	[3]
3S,4R-293B	DMVGDSM	Discovery agent	N.A.	Investigative	[3]
HMR-1556	DMXMTA9	Discovery agent	N.A.	Investigative	[4]
IKs124	DMLY5IF	Discovery agent	N.A.	Investigative	[5]
L-735,821	DMY60MG	Discovery agent	N.A.	Investigative	[6]
ML277	DMQ98RS	Discovery agent	N.A.	Investigative	[7]
N-(2-Diethylamino-ethyl)-4-hexyloxy-benzamide	DMZ4A2X	Discovery agent	N.A.	Investigative	[8]
N-(3,3-Dimethyl-butyl)-4-hexyloxy-benzamide	DM2Y5AP	Discovery agent	N.A.	Investigative	[8]
N-(3,3-Dimethyl-butyl)-4-indol-1-yl-benzamide	DMEUXOQ	Discovery agent	N.A.	Investigative	[8]
N-(3,3-Dimethyl-cyclopentyl)-4-hexyloxy-benzamide	DM6EJQ4	Discovery agent	N.A.	Investigative	[8]
R-L3	DMGEDQJ	Discovery agent	N.A.	Investigative	[9]
XE991	DMLH1PK	Discovery agent	N.A.	Investigative	[10]
zinc pyrithione	DMF0CRA	Discovery agent	N.A.	Investigative	[11]

References

• [1] Indapamide induces apoptosis of GH3 pituitary cells independently of its inhibition of voltage-dependent K+ currents. Eur J Pharmacol. 2006 Apr 24;536(1-2):78-84.
• [2] Class III antiarrhythmic activity in vivo by selective blockade of the slowly activating cardiac delayed rectifier potassium current IKs by (R)-2-(... J Med Chem. 1997 Nov 21;40(24):3865-8.
• [3] A kinetic study on the stereospecific inhibition of KCNQ1 and I(Ks) by the chromanol 293B. Br J Pharmacol. 2001 Dec;134(8):1647-54.
• [4] Selective optimization of side activities: another way for drug discovery. J Med Chem. 2004 Mar 11;47(6):1303-14.
• [5] Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells. J Physiol. 2004 Dec 1;561(Pt 2):547-57.
• [6] Molecular determinants of KCNQ1 channel block by a benzodiazepine. Mol Pharmacol. 2003 Jul;64(1):70-7.
• [7] Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator. Bioorg Med Chem Lett. 2012 Sep 15;22(18):5936-41.
• [8] Design and synthesis of 4-substituted benzamides as potent, selective, and orally bioavailable I(Ks) blockers. J Med Chem. 2001 Nov 8;44(23):3764-7.
• [9] A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. Mol Pharmacol. 1998 Jul;54(1):220-30.
• [10] Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991. Mol Pharmacol. 2000 Jun;57(6):1218-23.
• [11] Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants. Nat Chem Biol. 2007 May;3(5):287-96.