Details of the Drug Transporter (DTP)

General Information of Drug Transporter (DTP) (ID: DTO1UQY)

• DTP Name: Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 (SLC12A1)
• Gene Name: SLC12A1
• UniProt ID: Q13621 (S12A1_HUMAN)
• VARIDT ID: DTD0082
• Synonyms: BSC1; Kidney-specific Na-K-Cl symporter; NKCC2; SLC12A1; Solute carrier family 12 member 1
• DTP Family: Cation-Chloride Cotransporter (CCC) Family
• Tissue Specificity: Kidney specific.
• Sequence:
  MSLNNSSNVFLDSVPSNTNRFQVSVINENHESSAAADDNTDPPHYEETSFGDEAQKRLRI
  SFRPGNQECYDNFLQSGETAKTDASFHAYDSHTNTYYLQTFGHNTMDAVPKIEYYRNTGS
  ISGPKVNRPSLLEIHEQLAKNVAVTPSSADRVANGDGIPGDEQAENKEDDQAGVVKFGWV
  KGVLVRCMLNIWGVMLFIRLSWIVGEAGIGLGVLIILLSTMVTSITGLSTSAIATNGFVR
  GGGAYYLISRSLGPEFGGSIGLIFAFANAVAVAMYVVGFAETVVDLLKESDSMMVDPTND
  IRIIGSITVVILLGISVAGMEWEAKAQVILLVILLIAIANFFIGTVIPSNNEKKSRGFFN
  YQASIFAENFGPRFTKGEGFFSVFAIFFPAATGILAGANISGDLEDPQDAIPRGTMLAIF
  ITTVAYLGVAICVGACVVRDATGNMNDTIISGMNCNGSAACGLGYDFSRCRHEPCQYGLM
  NNFQVMSMVSGFGPLITAGIFSATLSSALASLVSAPKVFQALCKDNIYKALQFFAKGYGK
  NNEPLRGYILTFLIAMAFILIAELNTIAPIISNFFLASYALINFSCFHASYAKSPGWRPA
  YGIYNMWVSLFGAVLCCAVMFVINWWAAVITYVIEFFLYVYVTCKKPDVNWGSSTQALSY
  VSALDNALELTTVEDHVKNFRPQCIVLTGGPMTRPALLDITHAFTKNSGLCICCEVFVGP
  RKLCVKEMNSGMAKKQAWLIKNKIKAFYAAVAADCFRDGVRSLLQASGLGRMKPNTLVIG
  YKKNWRKAPLTEIENYVGIIHDAFDFEIGVVIVRISQGFDISQVLQVQEELERLEQERLA
  LEATIKDNECEEESGGIRGLFKKAGKLNITKTTPKKDGSINTSQSMHVGEFNQKLVEAST
  QFKKKQEKGTIDVWWLFDDGGLTLLIPYILTLRKKWKDCKLRIYVGGKINRIEEEKIVMA
  SLLSKFRIKFADIHIIGDINIRPNKESWKVFEEMIEPYRLHESCKDLTTAEKLKRETPWK
  ITDAELEAVKEKSYRQVRLNELLQEHSRAANLIVLSLPVARKGSISDLLYMAWLEILTKN
  LPPVLLVRGNHKNVLTFYS
• Function: This transporter mediates sodium and chloride reabsorption and plays a vital role in the regulation of ionic balance and cell volume.
• Endogenous Substrate(s): NaCl
• TCDB ID: 2.A.30.1.2
• Gene ID: 6557
• Reactome Pathway:
  Defective SLC12A1 causes Bartter syndrome 1 (BS1) (R-HSA-5619104)
  Cation-coupled Chloride cotransporters (R-HSA-426117)

Molecular Interaction Atlas (MIA) of This DTP

2 Approved Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Potassium Chloride	DMMTAJC	Hypokalemia	5C77	Approved	[13]
Sodium chloride	DMM3950	Skin burns	ME65.0	Approved	[14]

Molecular Expression Atlas (MEA) of This DTP

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2B33.1	Bone marrow	9.38E-01	8.74E-03	6.38E-02
Adrenocortical carcinoma	2D11.Z	Kidney	8.01E-01	-2.96E-02	-2.82E-01
Alopecia	ED70	Skin from scalp	1.73E-01	5.26E-02	3.06E-01
Alzheimer's disease	8A20	Entorhinal cortex	9.22E-01	1.78E-02	1.67E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	7.34E-02	-1.86E-01	-1.14E+00
Aortic stenosis	BB70	Calcified aortic valve	8.75E-01	-4.28E-02	-5.31E-02
Apnea	7A40	Hyperplastic tonsil	4.77E-01	3.45E-03	1.20E-02
Arthropathy	FA00-FA5Z	Peripheral blood	4.86E-01	4.29E-02	3.37E-01
Asthma	CA23	Nasal and bronchial airway	3.83E-04	-1.20E-01	-3.68E-01
Atopic dermatitis	EA80	Skin	2.78E-07	1.24E-01	2.71E+00
Autism	6A02	Whole blood	7.87E-03	-3.46E-02	-2.40E-01
Autoimmune uveitis	9A96	Peripheral monocyte	1.06E-01	-7.52E-02	-6.20E-01
Autosomal dominant monocytopenia	4B04	Whole blood	1.91E-02	1.29E-01	1.34E+00
Bacterial infection of gingival	1C1H	Gingival tissue	8.35E-02	4.72E-02	2.76E-01
Batten disease	5C56.1	Whole blood	5.53E-01	6.31E-02	6.35E-01
Behcet's disease	4A62	Peripheral blood	1.52E-01	3.62E-02	5.34E-01
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	8.74E-01	-1.27E-02	-9.00E-02
Bladder cancer	2C94	Bladder tissue	1.97E-14	7.11E-01	9.29E+00
Breast cancer	2C60-2C6Z	Breast tissue	3.96E-07	-5.54E-02	-2.25E-01
Cardioembolic stroke	8B11.20	Whole blood	4.93E-01	7.10E-02	1.03E-01
Cervical cancer	2C77	Cervical tissue	8.39E-04	3.58E-02	3.15E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	9.59E-02	6.24E-02	4.12E-01
Chronic hepatitis C	1E51.1	Whole blood	1.27E-01	-1.60E-02	-1.36E-01
Chronic obstructive pulmonary disease	CA22	Lung tissue	1.89E-01	1.81E-02	1.31E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	4.27E-02	3.91E-02	3.08E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	6.42E-01	1.84E-02	2.61E-01
Colon cancer	2B90	Colon tissue	9.64E-04	-7.52E-02	-4.20E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	4.89E-01	-3.70E-02	-1.50E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	8.46E-01	-5.71E-02	-4.02E-01
Endometriosis	GA10	Endometrium tissue	3.43E-01	1.67E-02	5.03E-02
Familial hypercholesterolemia	5C80.00	Peripheral blood	3.30E-01	1.06E-02	1.63E-01
Familial hypercholesterolemia	5C80.00	Whole blood	8.34E-03	-7.52E-02	-5.72E-01
Gastric cancer	2B72	Gastric tissue	6.39E-01	-6.73E-02	-4.21E-01
Glioblastopma	2A00.00	Nervous tissue	1.87E-01	-1.01E-01	-4.48E-01
Glioma	2A00.0Y-2A00.0Z	White matter tissue	1.24E-04	-5.16E-01	-2.27E+00
Head and neck cancer	2D42	Head and neck tissue	9.13E-01	2.01E-03	1.38E-02
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	4.81E-01	-8.03E-02	-5.76E-01
Huntington's disease	8A01.10	Whole blood	4.00E-01	3.13E-02	3.36E-01
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	3.99E-01	-3.00E-02	-1.13E-01
Immunodeficiency	4A00-4A20	Peripheral blood	7.81E-01	-3.57E-02	-4.25E-01
Influenza	1.00E+30	Whole blood	2.39E-02	3.45E-01	2.75E+00
Interstitial cystitis	GC00.3	Bladder tissue	1.83E-02	1.28E-01	1.95E+00
Intracranial aneurysm	8B01.0	Intracranial artery	1.31E-01	1.27E-01	7.36E-01
Irritable bowel syndrome	DD91.0	Rectal colon tissue	3.85E-01	1.75E-01	4.59E-01
Ischemic stroke	8B11	Peripheral blood	8.60E-01	-1.43E-02	-1.41E-01
Juvenile idiopathic arthritis	FA24	Peripheral blood	3.25E-01	1.10E-01	3.05E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	6.16E-01	-6.00E-03	-4.36E-02
Lateral sclerosis	8B60.4	Skin	5.31E-01	1.36E-03	1.74E-02
Liver cancer	2C12.0	Liver tissue	4.18E-07	3.13E-02	1.01E-01
Liver failure	DB99.7-DB99.8	Liver tissue	9.76E-01	3.56E-02	1.50E-01
Lung cancer	2C25	Lung tissue	1.77E-02	6.09E-02	3.50E-01
Lupus erythematosus	4A40	Whole blood	7.50E-03	-8.71E-02	-2.43E-01
Major depressive disorder	6A70-6A7Z	Whole blood	3.94E-01	8.57E-02	1.40E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	3.03E-01	2.45E-02	1.88E-01
Melanoma	2C30	Skin	9.85E-01	1.08E-01	2.54E-01
Multiple myeloma	2A83.1	Bone marrow	1.03E-05	-5.56E-01	-4.26E+00
Multiple myeloma	2A83.1	Peripheral blood	6.01E-01	5.43E-02	2.37E-01
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	7.35E-01	3.87E-02	1.60E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	5.11E-01	8.19E-02	5.15E-01
Myelofibrosis	2A20.2	Whole blood	1.67E-04	8.42E-02	7.93E-01
Myocardial infarction	BA41-BA50	Peripheral blood	6.84E-01	1.61E-01	3.55E-01
Myopathy	8C70.6	Muscle tissue	8.74E-04	-2.11E-01	-2.44E+00
Neonatal sepsis	KA60	Whole blood	6.28E-01	-1.48E-02	-7.23E-02
Neuroectodermal tumour	2A00.11	Brain stem tissue	8.48E-06	2.21E-01	1.52E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	2.74E-01	-3.40E-02	-3.52E-01
Obesity related type 2 diabetes	5A11	Omental adipose tissue	6.36E-03	1.74E-01	3.32E+00
Olive pollen allergy	CA08.00	Peripheral blood	3.03E-02	1.04E-01	1.58E+00
Oral cancer	2B6E	Oral tissue	3.10E-04	-1.64E-01	-4.61E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	1.63E-01	-1.99E-01	-8.54E-01
Osteoporosis	FB83.1	Bone marrow	1.95E-01	7.31E-02	8.13E-01
Ovarian cancer	2C73	Ovarian tissue	3.20E-01	9.78E-03	3.72E-02
Pancreatic cancer	2C10	Pancreas	8.12E-02	-1.82E-01	-6.34E-01
Parkinson's disease	8A00.0	Substantia nigra tissue	5.20E-01	-6.29E-02	-3.95E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	4.28E-02	-6.79E-02	-5.35E-01
Pituitary cancer	2D12	Pituitary tissue	2.93E-06	1.09E+00	3.79E+00
Pituitary gonadotrope tumour	2D12	Pituitary tissue	4.89E-06	1.24E+00	3.04E+00
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	4.13E-01	-8.87E-02	-6.78E-01
Polycythemia vera	2A20.4	Whole blood	3.85E-04	9.95E-02	8.71E-01
Pompe disease	5C51.3	Biceps muscle	8.23E-03	-9.69E-02	-8.59E-01
Preterm birth	KA21.4Z	Myometrium	7.40E-01	-1.13E-02	-1.70E-01
Prostate cancer	2C82	Prostate	4.85E-11	3.93E-01	1.80E+00
Psoriasis	EA90	Skin	1.59E-01	-4.70E-03	-2.67E-02
Rectal cancer	2B92	Rectal colon tissue	5.64E-01	-9.14E-02	-8.77E-01
Renal cancer	2C90-2C91	Kidney	8.19E-10	-5.21E+00	-6.82E+00
Retinoblastoma	2D02.2	Uvea	1.89E-02	-1.58E-01	-3.45E+00
Rheumatoid arthritis	FA20	Synovial tissue	8.94E-04	-4.11E-01	-2.28E+00
Rhinovirus infection	CA42.1	Nasal epithelium tissue	9.40E-01	-1.46E-03	-2.11E-02
Schizophrenia	6A20	Prefrontal cortex	1.04E-01	-4.58E-02	-2.22E-01
Schizophrenia	6A20	Superior temporal cortex	9.51E-01	1.05E-02	1.11E-01
Scleroderma	4A42.Z	Whole blood	1.55E-09	3.28E-01	4.92E+00
Seizure	8A60-8A6Z	Whole blood	8.93E-01	1.39E-02	1.23E-01
Sensitive skin	EK0Z	Skin	2.64E-01	-2.66E-02	-4.67E-01
Sepsis with septic shock	1G41	Whole blood	8.27E-01	-6.93E-03	-2.89E-02
Shwachman-Diamond syndrome	3A70.0	Bone marrow	5.06E-01	-3.37E-02	-1.64E-01
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	9.75E-01	-7.73E-02	-5.19E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	1.03E-01	8.96E-02	1.46E+00
Sjogren's syndrome	4A43.2	Salivary gland tissue	1.34E-01	-1.07E-01	-9.91E-01
Skin cancer	2C30-2C3Z	Skin	5.02E-31	2.55E-01	1.21E+00
Thrombocythemia	3B63	Whole blood	2.12E-02	1.15E-01	1.14E+00
Thrombocytopenia	3B64	Whole blood	8.42E-01	8.37E-03	4.85E-02
Thyroid cancer	2D10	Thyroid	4.11E-04	3.51E-02	2.12E-01
Tibial muscular dystrophy	8C75	Muscle tissue	6.34E-03	-1.85E-01	-1.23E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	8.63E-01	-1.05E-01	-1.39E+00
Type 2 diabetes	5A11	Liver tissue	3.52E-01	8.15E-02	9.75E-01
Ureter cancer	2C92	Urothelium	2.96E-01	-8.99E-02	-5.44E-01
Uterine cancer	2C78	Endometrium tissue	1.01E-08	1.27E-01	5.17E-01
Vitiligo	ED63.0	Skin	7.22E-01	-1.91E-02	-1.20E-01

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Solute carrier family 12 member 1 (SLC12A1) DTT Info
• DTP DTT Type: Successful

12 Approved Drug(s) Targeting This DTP

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

3 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Calyculin-A	DMY29Q8	Discovery agent	N.A.	Investigative	[10]
CL-301	DMW3RLB	Neurological disorder	6B60	Investigative	[11]
Piretanide	DM0SCDR	Discovery agent	N.A.	Investigative	[12]

References

• [1] Nongenomic effect of aldosterone on ion transport pathways of red blood cells. Cell Physiol Biochem. 2008;22(1-4):269-78.
• [2] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [3] 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.
• [4] 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.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] 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.
• [7] Update of diuretics in the treatment of hypertension. Am J Ther. 2007 Mar-Apr;14(2):154-60.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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).
• [12] 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.
• [13] Rare mutations in renal sodium and potassium transporter genes exhibit impaired transport function. Curr Opin Nephrol Hypertens. 2014 Jan;23(1):1-8.
• [14] Upregulation of renal sodium transporters in D5 dopamine receptor-deficient mice. Hypertension. 2010 Jun;55(6):1431-7.