Target Information

Target General Information

Target ID

T93878 (Former ID: TTDS00116)

Target 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

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Gene Name

SLC12A1

Target Type

Successful target

[1]

Disease

[+] 5 Target-related Diseases

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]

Function

Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.

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BioChemical Class

Cation-chloride cotransporter

UniProt ID

S12A1_HUMAN

Sequence

MSLNNSSNVFLDSVPSNTNRFQVSVINENHESSAAADDNTDPPHYEETSFGDEAQKRLRI
SFRPGNQECYDNFLQSGETAKTDASFHAYDSHTNTYYLQTFGHNTMDAVPKIEYYRNTGS
ISGPKVNRPSLLEIHEQLAKNVAVTPSSADRVANGDGIPGDEQAENKEDDQAGVVKFGWV
KGVLVRCMLNIWGVMLFIRLSWIVGEAGIGLGVLIILLSTMVTSITGLSTSAIATNGFVR
GGGAYYLISRSLGPEFGGSIGLIFAFANAVAVAMYVVGFAETVVDLLKESDSMMVDPTND
IRIIGSITVVILLGISVAGMEWEAKAQVILLVILLIAIANFFIGTVIPSNNEKKSRGFFN
YQASIFAENFGPRFTKGEGFFSVFAIFFPAATGILAGANISGDLEDPQDAIPRGTMLAIF
ITTVAYLGVAICVGACVVRDATGNMNDTIISGMNCNGSAACGLGYDFSRCRHEPCQYGLM
NNFQVMSMVSGFGPLITAGIFSATLSSALASLVSAPKVFQALCKDNIYKALQFFAKGYGK
NNEPLRGYILTFLIAMAFILIAELNTIAPIISNFFLASYALINFSCFHASYAKSPGWRPA
YGIYNMWVSLFGAVLCCAVMFVINWWAAVITYVIEFFLYVYVTCKKPDVNWGSSTQALSY
VSALDNALELTTVEDHVKNFRPQCIVLTGGPMTRPALLDITHAFTKNSGLCICCEVFVGP
RKLCVKEMNSGMAKKQAWLIKNKIKAFYAAVAADCFRDGVRSLLQASGLGRMKPNTLVIG
YKKNWRKAPLTEIENYVGIIHDAFDFEIGVVIVRISQGFDISQVLQVQEELERLEQERLA
LEATIKDNECEEESGGIRGLFKKAGKLNITKTTPKKDGSINTSQSMHVGEFNQKLVEAST
QFKKKQEKGTIDVWWLFDDGGLTLLIPYILTLRKKWKDCKLRIYVGGKINRIEEEKIVMA
SLLSKFRIKFADIHIIGDINIRPNKESWKVFEEMIEPYRLHESCKDLTTAEKLKRETPWK
ITDAELEAVKEKSYRQVRLNELLQEHSRAANLIVLSLPVARKGSISDLLYMAWLEILTKN
LPPVLLVRGNHKNVLTFYS

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3D Structure

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AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 12 Approved Drugs

Aldosterone

Drug Info

Approved

Hypertension

[2], [3]

Bendroflumethiazide

Drug Info

Approved

High blood pressure

[4], [5]

Bumetanide

Drug Info

Approved

Congestive heart failure

[6], [7]

Chlorthalidone

Drug Info

Approved

Edema

[8], [9], [10]

Ethacrynate Sodium

Drug Info

Approved

High blood pressure

[10]

Ethacrynic acid

Drug Info

Approved

High blood pressure

[11], [12]

Furosemide

Drug Info

Approved

Congestive heart failure

[13], [14]

Hydroflumethiazide

Drug Info

Approved

Congestive heart failure

[10], [15], [16]

Methyclothiazide

Drug Info

Approved

Edema

[10], [17], [18]

Potassium Chloride

Drug Info

Approved

Hypokalemia

[19]

Torasemide

Drug Info

Approved

Congestive heart failure

[20], [21]

Trichlormethiazide

Drug Info

Approved

Hypertension

[22], [23]

Mode of Action

[+] 2 Modes of Action

Blocker

[+] 12 Blocker drugs

Aldosterone

Drug Info

[24], [25]

Bendroflumethiazide

Drug Info

[26]

Bumetanide

Drug Info

[1], [27]

Chlorthalidone

Drug Info

[28]

Ethacrynic acid

Drug Info

[30], [31]

Furosemide

Drug Info

[32]

Hydroflumethiazide

Drug Info

[26]

Methyclothiazide

Drug Info

[26]

Torasemide

Drug Info

[33], [34], [35]

Trichlormethiazide

Drug Info

[36]

Calyculin-A

Drug Info

[37]

Piretanide

Drug Info

[39], [40], [41]

Modulator

[+] 3 Modulator drugs

Ethacrynate Sodium

Drug Info

[29]

Potassium Chloride

Drug Info

[29]

CL-301

Drug Info

[38]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Similarity Proteins

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Similarity Proteins

There is no similarity protein (E value < 0.005) for this target

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Salivary secretion

Pancreatic secretion

Vibrio cholerae infection

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Kidney Function

Reactome

[+] 1 Reactome Pathways

Cation-coupled Chloride cotransporters

WikiPathways

[+] 4 WikiPathways

miR-targeted genes in squamous cell - TarBase

miR-targeted genes in muscle cell - TarBase

miR-targeted genes in lymphocytes - TarBase

miR-targeted genes in epithelium - TarBase

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 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.

REF 2

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. (Ligand id: 2872).

REF 3

Treatment of hypertension with olmesartan medoxomil, alone and in combination with a diuretic: an update. J Hum Hypertens. 2007 Sep;21(9):699-708.

REF 4

REF 5

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 077833.

REF 6

REF 7

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 074225.

REF 8

REF 9

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 086831.

REF 10

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 11

REF 12

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 016092.

REF 13

REF 14

Targeting the kidney in acute decompensated heart failure: conventional diuretics and renal-acting vasodilators. Rev Cardiovasc Med. 2008 Winter;9(1):39-45.

REF 15

REF 16

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 088850.

REF 17

REF 18

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 087672.

REF 19

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 070999.

REF 20

REF 21

Drug information of Torasemide, 2008. eduDrugs.

REF 22

REF 23

Current usage of diuretics among hypertensive patients in Japan: the Japan Home versus Office Blood Pressure Measurement Evaluation (J-HOME) study. Hypertens Res. 2006 Nov;29(11):857-63.

REF 24

Nongenomic effect of aldosterone on ion transport pathways of red blood cells. Cell Physiol Biochem. 2008;22(1-4):269-78.

REF 25

Aldosterone regulates the Na-K-2Cl cotransporter in vascular smooth muscle. Hypertension. 2003 May;41(5):1131-5.

REF 26

DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.

REF 27

Effect of L-ascorbate on chloride transport in freshly excised sinonasal epithelia. Am J Rhinol Allergy. 2009 May-Jun;23(3):294-9.

REF 28

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.

REF 29

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 30

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.

REF 31

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.

REF 32

Update of diuretics in the treatment of hypertension. Am J Ther. 2007 Mar-Apr;14(2):154-60.

REF 33

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.

REF 34

Effects of loop diuretics on angiotensin II-stimulated vascular smooth muscle cell growth. Nephrol Dial Transplant. 2001;16 Suppl 1:14-7.

REF 35

Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats. Hypertension. 1999 Jul;34(1):138-43.

REF 36

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.

REF 37

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.

REF 38

REF 39

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.

REF 40

Rat NKCC2/NKCC1 cotransporter selectivity for loop diuretic drugs. Naunyn Schmiedebergs Arch Pharmacol. 2002 Mar;365(3):193-9.

REF 41

Piretanide, a potent diuretic with potassium-sparing properties, for the treatment of congestive heart failure. Clin Pharmacol Ther. 1986 Nov;40(5):587-94.

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