Details of the Drug Transporter (DTP)

General Information of Drug Transporter (DTP) (ID: DT0VAI5)

• DTP Name: Excitatory amino acid transporter 2 (SLC1A2)
• Gene Name: SLC1A2
• UniProt ID: P43004 (EAA2_HUMAN)
• VARIDT ID: DTD0130
• Synonyms: EAAT2; EIEE41; GLT-1; GLT1; Glutamate/aspartate transporter II; HBGT; SLC1A2; Sodium-dependent glutamate/aspartate transporter 2; Solute carrier family 1 member 2
• DTP Family: Dicarboxylate/Amino Acid:Cation (Na(+) Or H(+)) Symporter (DAACS) Family
• Sequence:
  MASTEGANNMPKQVEVRMHDSHLGSEEPKHRHLGLRLCDKLGKNLLLTLTVFGVILGAVC
  GGLLRLASPIHPDVVMLIAFPGDILMRMLKMLILPLIISSLITGLSGLDAKASGRLGTRA
  MVYYMSTTIIAAVLGVILVLAIHPGNPKLKKQLGPGKKNDEVSSLDAFLDLIRNLFPENL
  VQACFQQIQTVTKKVLVAPPPDEEANATSAVVSLLNETVTEVPEETKMVIKKGLEFKDGM
  NVLGLIGFFIAFGIAMGKMGDQAKLMVDFFNILNEIVMKLVIMIMWYSPLGIACLICGKI
  IAIKDLEVVARQLGMYMVTVIIGLIIHGGIFLPLIYFVVTRKNPFSFFAGIFQAWITALG
  TASSAGTLPVTFRCLEENLGIDKRVTRFVLPVGATINMDGTALYEAVAAIFIAQMNGVVL
  DGGQIVTVSLTATLASVGAASIPSAGLVTMLLILTAVGLPTEDISLLVAVDWLLDRMRTS
  VNVVGDSFGAGIVYHLSKSELDTIDSQHRVHEDIEMTKTQSIYDDMKNHRESNSNQCVYA
  AHNSVIVDECKVTLAANGKSADCSVEEEPWKREK
• Function: This sodium-dependent, high-affinity amino acid transporter functions as a symporter and mediates the uptake of L-glutamate and also L-aspartate and D-aspartate. Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport. Essential for the rapid removal of released glutamate from the synaptic cleft, and for terminating the postsynaptic action of glutamate.
• Endogenous Substrate(s): Na+; Aspartate
• TCDB ID: 2.A.23.2.7
• Gene ID: 6506
• KEGG Pathway:
  Synaptic vesicle cycle (hsa04721)
  Glutamatergic synapse (hsa04724)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
• Reactome Pathway:
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)
  Astrocytic Glutamate-Glutamine Uptake And Metabolism (R-HSA-210455)

Molecular Interaction Atlas (MIA) of This DTP

1 Approved Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-glutamic acid	DM4PUDW	Schizophrenia	6A20	Approved	[6]

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	1.15E-02	4.08E-02	3.01E-01
Adrenocortical carcinoma	2D11.Z	Kidney	5.96E-03	-3.54E-01	-6.28E-01
Alopecia	ED70	Skin from scalp	2.17E-01	7.66E-02	4.27E-01
Alzheimer's disease	8A20	Entorhinal cortex	6.18E-01	-1.12E-01	-1.17E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	1.31E-01	-3.93E-01	-6.67E-01
Aortic stenosis	BB70	Calcified aortic valve	3.14E-01	-1.24E-01	-7.25E-01
Apnea	7A40	Hyperplastic tonsil	2.45E-01	1.18E-01	9.79E-01
Arthropathy	FA00-FA5Z	Peripheral blood	8.53E-01	2.11E-03	2.17E-02
Asthma	CA23	Nasal and bronchial airway	9.17E-04	-3.95E-01	-7.33E-01
Atopic dermatitis	EA80	Skin	3.58E-01	9.63E-02	5.93E-01
Autism	6A02	Whole blood	3.91E-01	-3.91E-02	-2.15E-01
Autoimmune uveitis	9A96	Peripheral monocyte	6.36E-01	1.60E-02	3.02E-01
Autosomal dominant monocytopenia	4B04	Whole blood	2.71E-01	1.25E-01	1.34E+00
Bacterial infection of gingival	1C1H	Gingival tissue	1.57E-04	9.15E-02	7.33E-01
Batten disease	5C56.1	Whole blood	9.87E-01	6.37E-02	6.22E-01
Behcet's disease	4A62	Peripheral blood	9.47E-01	7.86E-03	3.92E-02
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	5.76E-01	7.81E-02	1.35E-01
Bladder cancer	2C94	Bladder tissue	3.28E-01	-4.52E-02	-1.50E-01
Breast cancer	2C60-2C6Z	Breast tissue	4.47E-09	4.24E-02	1.52E-01
Cardioembolic stroke	8B11.20	Whole blood	2.18E-02	7.74E-02	4.72E-01
Cervical cancer	2C77	Cervical tissue	8.67E-04	-2.93E-01	-1.01E+00
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	5.33E-01	1.88E-02	1.30E-01
Chronic hepatitis C	1E51.1	Whole blood	5.96E-01	2.85E-02	2.19E-01
Chronic obstructive pulmonary disease	CA22	Lung tissue	7.63E-02	1.03E-01	6.00E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	3.82E-01	1.05E-01	3.90E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	5.75E-01	-1.19E-02	-1.34E-01
Colon cancer	2B90	Colon tissue	7.48E-01	2.28E-02	1.04E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	8.40E-01	-1.16E-02	-1.12E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	7.60E-01	-1.05E-02	-1.11E-01
Endometriosis	GA10	Endometrium tissue	6.54E-02	-6.04E-02	-2.48E-01
Familial hypercholesterolemia	5C80.00	Peripheral blood	8.80E-01	-3.26E-02	-2.13E-01
Familial hypercholesterolemia	5C80.00	Whole blood	9.08E-02	-4.92E-02	-2.88E-01
Gastric cancer	2B72	Gastric tissue	9.05E-02	-7.93E-01	-2.21E+00
Glioblastopma	2A00.00	Nervous tissue	1.28E-77	-2.93E+00	-1.73E+00
Glioma	2A00.0Y-2A00.0Z	White matter tissue	2.06E-01	8.29E-01	9.24E-01
Head and neck cancer	2D42	Head and neck tissue	7.82E-10	-1.91E-01	-7.01E-01
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	2.39E-01	-5.49E-01	-4.59E-01
Huntington's disease	8A01.10	Whole blood	7.27E-01	1.55E-02	1.43E-01
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	3.70E-01	9.83E-02	7.14E-01
Immunodeficiency	4A00-4A20	Peripheral blood	3.56E-01	5.76E-02	5.27E-01
Influenza	1.00E+30	Whole blood	4.86E-02	-3.31E-01	-2.20E+00
Interstitial cystitis	GC00.3	Bladder tissue	4.53E-01	4.13E-02	3.16E-01
Intracranial aneurysm	8B01.0	Intracranial artery	9.31E-01	-1.07E-02	-7.78E-02
Irritable bowel syndrome	DD91.0	Rectal colon tissue	6.74E-02	1.38E-01	4.93E-01
Ischemic stroke	8B11	Peripheral blood	4.58E-02	5.89E-02	6.19E-01
Juvenile idiopathic arthritis	FA24	Peripheral blood	1.75E-02	6.76E-02	2.44E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	5.96E-01	7.23E-02	1.97E-01
Lateral sclerosis	8B60.4	Skin	6.42E-02	1.58E-01	1.60E+00
Liver cancer	2C12.0	Liver tissue	2.81E-04	-8.12E-01	-8.62E-01
Liver failure	DB99.7-DB99.8	Liver tissue	1.39E-02	-6.46E-01	-1.24E+00
Lung cancer	2C25	Lung tissue	1.45E-01	-7.14E-02	-4.42E-01
Lupus erythematosus	4A40	Whole blood	3.02E-01	-5.00E-02	-2.23E-01
Major depressive disorder	6A70-6A7Z	Whole blood	3.57E-03	1.03E-01	6.26E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	8.32E-02	-2.27E-01	-3.86E-01
Melanoma	2C30	Skin	3.67E-03	-1.59E-01	-4.98E-01
Multiple myeloma	2A83.1	Bone marrow	2.39E-02	-2.28E-01	-1.07E+00
Multiple myeloma	2A83.1	Peripheral blood	8.99E-02	9.74E-02	1.46E+00
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	1.83E-01	1.12E-01	7.01E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	2.05E-01	-8.41E-03	-7.93E-02
Myelofibrosis	2A20.2	Whole blood	1.68E-02	2.46E-01	1.80E+00
Myocardial infarction	BA41-BA50	Peripheral blood	5.03E-01	5.47E-02	1.70E-01
Myopathy	8C70.6	Muscle tissue	5.04E-01	5.52E-02	3.82E-01
Neonatal sepsis	KA60	Whole blood	3.68E-02	4.29E-02	2.36E-01
Neuroectodermal tumour	2A00.11	Brain stem tissue	2.58E-08	-2.55E+00	-4.52E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	4.12E-01	1.14E-01	1.27E-01
Obesity related type 2 diabetes	5A11	Omental adipose tissue	1.90E-02	1.94E-01	2.12E+00
Olive pollen allergy	CA08.00	Peripheral blood	3.83E-01	-2.69E-01	-6.38E-01
Oral cancer	2B6E	Oral tissue	8.40E-03	-1.95E-01	-4.97E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	6.99E-02	-2.05E-01	-9.60E-01
Osteoporosis	FB83.1	Bone marrow	9.11E-01	9.32E-03	1.08E-01
Ovarian cancer	2C73	Ovarian tissue	1.13E-01	9.34E-02	4.65E-01
Pancreatic cancer	2C10	Pancreas	4.19E-04	-9.63E-01	-1.19E+00
Parkinson's disease	8A00.0	Substantia nigra tissue	2.27E-01	-4.22E-01	-8.74E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	9.68E-01	8.92E-03	1.03E-01
Pituitary cancer	2D12	Pituitary tissue	7.66E-01	3.85E-02	1.65E-01
Pituitary gonadotrope tumour	2D12	Pituitary tissue	3.43E-01	-1.61E-03	-6.03E-03
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	9.81E-01	3.35E-02	3.17E-01
Polycythemia vera	2A20.4	Whole blood	1.67E-11	1.88E-01	1.40E+00
Pompe disease	5C51.3	Biceps muscle	2.18E-01	-6.50E-02	-4.92E-01
Preterm birth	KA21.4Z	Myometrium	1.83E-02	-2.08E-01	-1.30E+00
Prostate cancer	2C82	Prostate	3.33E-02	-2.30E-01	-7.68E-01
Psoriasis	EA90	Skin	1.29E-10	-1.83E-01	-7.93E-01
Rectal cancer	2B92	Rectal colon tissue	3.93E-01	-1.90E-01	-9.88E-01
Renal cancer	2C90-2C91	Kidney	3.02E-01	-1.12E-01	-1.09E+00
Retinoblastoma	2D02.2	Uvea	1.07E-13	-4.19E+00	-6.64E+00
Rheumatoid arthritis	FA20	Synovial tissue	2.10E-02	-2.25E-01	-9.98E-01
Rhinovirus infection	CA42.1	Nasal epithelium tissue	4.06E-01	-1.24E-02	-1.53E-01
Schizophrenia	6A20	Prefrontal cortex	1.33E-01	-3.63E-01	-1.49E-01
Schizophrenia	6A20	Superior temporal cortex	9.70E-01	4.45E-02	9.88E-02
Scleroderma	4A42.Z	Whole blood	8.83E-01	1.54E-02	1.35E-01
Seizure	8A60-8A6Z	Whole blood	5.89E-01	-1.49E-02	-8.16E-02
Sensitive skin	EK0Z	Skin	3.64E-01	5.37E-02	5.87E-01
Sepsis with septic shock	1G41	Whole blood	5.20E-03	6.95E-02	3.27E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	6.53E-02	2.79E-01	8.57E-01
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	2.23E-01	6.38E-02	3.75E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	4.92E-01	1.23E-01	8.78E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	5.60E-01	2.03E-01	4.62E-01
Skin cancer	2C30-2C3Z	Skin	1.82E-31	-3.47E-01	-1.44E+00
Thrombocythemia	3B63	Whole blood	1.17E-04	1.63E-01	1.20E+00
Thrombocytopenia	3B64	Whole blood	6.78E-01	-4.11E-03	-5.28E-02
Thyroid cancer	2D10	Thyroid	9.79E-05	-1.34E-01	-5.58E-01
Tibial muscular dystrophy	8C75	Muscle tissue	1.17E-01	-9.54E-02	-5.74E-01
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	2.43E-02	-2.12E+00	-6.86E+00
Type 2 diabetes	5A11	Liver tissue	3.35E-02	-2.15E-01	-6.53E-01
Ureter cancer	2C92	Urothelium	1.18E-01	-5.45E-02	-6.99E-01
Uterine cancer	2C78	Endometrium tissue	4.91E-19	-2.62E-01	-1.06E+00
Vitiligo	ED63.0	Skin	7.92E-02	1.23E-01	6.44E-01

Drug Affinity of This DTP Assessed by Cell Line

Approved Drug(s)

Drug Name	Highest Status	Cell Line	Affinity	REF
L-glutamic acid	Approved	Human embryonic kidney cells (HEK293)-EAAT2	Km = 21 microM	[7]
L-glutamic acid	Approved	Human embryonic kidney cells (HEK293)-EAAT2	Km = 21 microM	[8]

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Excitatory amino acid transporter 2 (SLC1A2) DTT Info
• DTP DTT Type: Literature-reported

6 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
D-aspartic acid	DM7Z892	Discovery agent	N.A.	Investigative	[1]
DL-TBOA	DM2HGNU	Discovery agent	N.A.	Investigative	[2]
SYM2081	DM30WDL	Discovery agent	N.A.	Investigative	[3], [1]
Threo-3-methylglutamate	DMOE3IJ	Discovery agent	N.A.	Investigative	[3]
WAY-213613	DMMXL4E	Discovery agent	N.A.	Investigative	[4]
[3H]ETB-TBOA	DMWGY61	Discovery agent	N.A.	Investigative	[5]

References

• [1] 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: 869).
• [2] DL-threo-beta-benzyloxyaspartate, a potent blocker of excitatory amino acid transporters. Mol Pharmacol. 1998 Feb;53(2):195-201.
• [3] Contrasting modes of action of methylglutamate derivatives on the excitatory amino acid transporters, EAAT1 and EAAT2. Mol Pharmacol. 1997 May;51(5):809-15.
• [4] Characterization of novel aryl-ether, biaryl, and fluorene aspartic acid and diaminopropionic acid analogs as potent inhibitors of the high-affinit... Mol Pharmacol. 2005 Oct;68(4):974-82.
• [5] Characterization of the tritium-labeled analog of L-threo-beta-benzyloxyaspartate binding to glutamate transporters. Mol Pharmacol. 2007 Jan;71(1):294-302.
• [6] EAAT2 (GLT-1; slc1a2) glutamate transporters reconstituted in liposomes argues against heteroexchange being substantially faster than net uptake. J Neurosci. 2014 Oct 1;34(40):13472-85.
• [7] Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3. J Med Chem. 2005 Dec 15;48(25):7980-92.
• [8] Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3. J Med Chem. 2006 Nov 2;49(22):6532-8.