Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTS087L)

• DTT Name: Solute carrier family 12 member 1 (SLC12A1)
• Synonyms: Solute carrier family 12 member; SLC12A1; Na+/K+/2CL- co-transporter; NKCC2; Kidney-specific Na-K-Cl symporter; Bumetanide-sensitive sodium-(potassium)Solute carrier family 12 member 1-chloride cotransporter 2; Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2
• Gene Name: SLC12A1
• DTT Type: Successful target; [1]
• Related Disease:
  Essential hypertension [ICD-11: BA00]
  Heart failure [ICD-11: BD10-BD1Z]
  Hypertension [ICD-11: BA00-BA04]
  Hypo-kalaemia [ICD-11: 5C77]
  Oedema [ICD-11: MG29]
• BioChemical Class: Cation-chloride cotransporter
• UniProt ID: S12A1_HUMAN
• TTD ID: T93878
• Sequence:
  MSLNNSSNVFLDSVPSNTNRFQVSVINENHESSAAADDNTDPPHYEETSFGDEAQKRLRI
  SFRPGNQECYDNFLQSGETAKTDASFHAYDSHTNTYYLQTFGHNTMDAVPKIEYYRNTGS
  ISGPKVNRPSLLEIHEQLAKNVAVTPSSADRVANGDGIPGDEQAENKEDDQAGVVKFGWV
  KGVLVRCMLNIWGVMLFIRLSWIVGEAGIGLGVLIILLSTMVTSITGLSTSAIATNGFVR
  GGGAYYLISRSLGPEFGGSIGLIFAFANAVAVAMYVVGFAETVVDLLKESDSMMVDPTND
  IRIIGSITVVILLGISVAGMEWEAKAQVILLVILLIAIANFFIGTVIPSNNEKKSRGFFN
  YQASIFAENFGPRFTKGEGFFSVFAIFFPAATGILAGANISGDLEDPQDAIPRGTMLAIF
  ITTVAYLGVAICVGACVVRDATGNMNDTIISGMNCNGSAACGLGYDFSRCRHEPCQYGLM
  NNFQVMSMVSGFGPLITAGIFSATLSSALASLVSAPKVFQALCKDNIYKALQFFAKGYGK
  NNEPLRGYILTFLIAMAFILIAELNTIAPIISNFFLASYALINFSCFHASYAKSPGWRPA
  YGIYNMWVSLFGAVLCCAVMFVINWWAAVITYVIEFFLYVYVTCKKPDVNWGSSTQALSY
  VSALDNALELTTVEDHVKNFRPQCIVLTGGPMTRPALLDITHAFTKNSGLCICCEVFVGP
  RKLCVKEMNSGMAKKQAWLIKNKIKAFYAAVAADCFRDGVRSLLQASGLGRMKPNTLVIG
  YKKNWRKAPLTEIENYVGIIHDAFDFEIGVVIVRISQGFDISQVLQVQEELERLEQERLA
  LEATIKDNECEEESGGIRGLFKKAGKLNITKTTPKKDGSINTSQSMHVGEFNQKLVEAST
  QFKKKQEKGTIDVWWLFDDGGLTLLIPYILTLRKKWKDCKLRIYVGGKINRIEEEKIVMA
  SLLSKFRIKFADIHIIGDINIRPNKESWKVFEEMIEPYRLHESCKDLTTAEKLKRETPWK
  ITDAELEAVKEKSYRQVRLNELLQEHSRAANLIVLSLPVARKGSISDLLYMAWLEILTKN
  LPPVLLVRGNHKNVLTFYS
• Function: Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.
• KEGG Pathway:
  Salivary secretion (hsa04970)
  Pancreatic secretion (hsa04972)
  Vibrio cholerae infection (hsa05110)
• Reactome Pathway: Cation-coupled Chloride cotransporters (R-HSA-426117)

Molecular Interaction Atlas (MIA) of This DTT

12 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aldosterone	DM9S2JW	Hypertension	BA00-BA04	Approved	[2], [3]
Bendroflumethiazide	DM7EVLC	High blood pressure	BA00	Approved	[4]
Bumetanide	DMRV7H0	Congestive heart failure	BD10	Approved	[1], [5]
Chlorthalidone	DM4DMBT	Edema	MG29	Approved	[6]
Ethacrynate sodium	DM5M4NT	High blood pressure	BA00	Approved	[7]
Ethacrynic acid	DM60QMR	High blood pressure	BA00	Approved	[8], [9]
Furosemide	DMMQ8ZG	Congestive heart failure	BD10	Approved	[10]
Hydroflumethiazide	DMVPUQI	Congestive heart failure	BD10	Approved	[4]
Methyclothiazide	DMN7SDE	Edema	MG29	Approved	[4]
Potassium chloride	DMMTAJC	Hypokalemia	5C77	Approved	[7]
Torasemide	DMXKJ6C	Congestive heart failure	BD10	Approved	[11], [12], [13]
Trichlormethiazide	DMHAQCO	Hypertension	BA00-BA04	Approved	[14]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Calyculin-A	DMY29Q8	Discovery agent	N.A.	Investigative	[15]
CL-301	DMW3RLB	Neurological disorder	6B60	Investigative	[16]
Piretanide	DM0SCDR	Discovery agent	N.A.	Investigative	[17], [18], [19]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 (SLC12A1) DTP Info
• Gene Name: SLC12A1

2 Approved Drug(s) Transported by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Potassium chloride	DMMTAJC	Hypokalemia	5C77	Approved	[20]
Sodium chloride	DMM3950	Skin burns	ME65.0	Approved	[21]

References

• [1] Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release. J Biol Chem. 2009 Mar 27;284(13):8726-37.
• [2] Nongenomic effect of aldosterone on ion transport pathways of red blood cells. Cell Physiol Biochem. 2008;22(1-4):269-78.
• [3] Aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle. Hypertension. 2003 May;41(5):1131-5.
• [4] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [5] Effect of L-ascorbate on chloride transport in freshly excised sinonasal epithelia. Am J Rhinol Allergy. 2009 May-Jun;23(3):294-9.
• [6] The 45-year story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol. 2004 Mar 31;217(1-2):45-52.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [8] Na-K-Cl cotransport regulates intracellular volume and monolayer permeability of trabecular meshwork cells. Am J Physiol. 1995 Apr;268(4 Pt 1):C1067-74.
• [9] Inhibition of Na-K-2Cl cotransport and bumetanide binding by ethacrynic acid, its analogues, and adducts. Am J Physiol. 1993 May;264(5 Pt 1):C1270-7.
• [10] Update of diuretics in the treatment of hypertension. Am J Ther. 2007 Mar-Apr;14(2):154-60.
• [11] Genetic variation in the renal sodium transporters NKCC2, NCC, and ENaC in relation to the effects of loop diuretic drugs. Clin Pharmacol Ther. 2007 Sep;82(3):300-9.
• [12] Effects of loop diuretics on angiotensin II-stimulated vascular smooth muscle cell growth. Nephrol Dial Transplant. 2001;16 Suppl 1:14-7.
• [13] Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats. Hypertension. 1999 Jul;34(1):138-43.
• [14] Function and regulation of epithelial sodium transporters in the kidney of a salt-sensitive hypertensive rat model. J Hypertens. 2007 May;25(5):1065-72.
• [15] Involvement of K(+)-Cl(-)-cotransport in the apoptosis induced by N-ethylmaleimide in HepG2 human hepatoblastoma cells. Eur J Pharmacol. 2001 Apr 20;418(1-2):1-5.
• [16] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 969).
• [17] Peripheral and central antinociceptive action of Na+-K+-2Cl- cotransporter blockers on formalin-induced nociception in rats. Pain. 2005 Mar;114(1-2):231-8.
• [18] Rat NKCC2/NKCC1 cotransporter selectivity for loop diuretic drugs. Naunyn Schmiedebergs Arch Pharmacol. 2002 Mar;365(3):193-9.
• [19] Piretanide, a potent diuretic with potassium-sparing properties, for the treatment of congestive heart failure. Clin Pharmacol Ther. 1986 Nov;40(5):587-94.
• [20] Rare mutations in renal sodium and potassium transporter genes exhibit impaired transport function. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):1-8.
• [21] Upregulation of renal sodium transporters in D5 dopamine receptor-deficient mice. Hypertension. 2010 Jun;55(6):1431-7.