Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBA2M8Y)

DOT Name Solute carrier family 12 member 5 (SLC12A5)
Synonyms Electroneutral potassium-chloride cotransporter 2; K-Cl cotransporter 2; hKCC2; Neuronal K-Cl cotransporter
Gene Name SLC12A5
Related Disease
Developmental and epileptic encephalopathy, 34 ( )
Malignant migrating partial seizures of infancy ( )
Epilepsy, idiopathic generalized, susceptibility to, 14 ( )
Infantile spasm ( )
UniProt ID
S12A5_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
6M23; 7D8Z
Pfam ID
PF00324 ; PF03522
Sequence
MSRRFTVTSLPPAGPARSPDPESRRHSVADPRHLPGEDVKGDGNPKESSPFINSTDTEKG
KEYDGKNMALFEEEMDTSPMVSSLLSGLANYTNLPQGSREHEEAENNEGGKKKPVQAPRM
GTFMGVYLPCLQNIFGVILFLRLTWVVGIAGIMESFCMVFICCSCTMLTAISMSAIATNG
VVPAGGSYYMISRSLGPEFGGAVGLCFYLGTTFAGAMYILGTIEILLAYLFPAMAIFKAE
DASGEAAAMLNNMRVYGTCVLTCMATVVFVGVKYVNKFALVFLGCVILSILAIYAGVIKS
AFDPPNFPICLLGNRTLSRHGFDVCAKLAWEGNETVTTRLWGLFCSSRFLNATCDEYFTR
NNVTEIQGIPGAASGLIKENLWSSYLTKGVIVERSGMTSVGLADGTPIDMDHPYVFSDMT
SYFTLLVGIYFPSVTGIMAGSNRSGDLRDAQKSIPTGTILAIATTSAVYISSVVLFGACI
EGVVLRDKFGEAVNGNLVVGTLAWPSPWVIVIGSFFSTCGAGLQSLTGAPRLLQAISRDG
IVPFLQVFGHGKANGEPTWALLLTACICEIGILIASLDEVAPILSMFFLMCYMFVNLACA
VQTLLRTPNWRPRFRYYHWTLSFLGMSLCLALMFICSWYYALVAMLIAGLIYKYIEYRGA
EKEWGDGIRGLSLSAARYALLRLEEGPPHTKNWRPQLLVLVRVDQDQNVVHPQLLSLTSQ
LKAGKGLTIVGSVLEGTFLENHPQAQRAEESIRRLMEAEKVKGFCQVVISSNLRDGVSHL
IQSGGLGGLQHNTVLVGWPRNWRQKEDHQTWRNFIELVRETTAGHLALLVTKNVSMFPGN
PERFSEGSIDVWWIVHDGGMLMLLPFLLRHHKVWRKCKMRIFTVAQMDDNSIQMKKDLTT
FLYHLRITAEVEVVEMHESDISAYTYEKTLVMEQRSQILKQMHLTKNEREREIQSITDES
RGSIRRKNPANTRLRLNVPEETAGDSEEKPEEEVQLIHDQSAPSCPSSSPSPGEEPEGEG
ETDPEKVHLTWTKDKSVAEKNKGPSPVSSEGIKDFFSMKPEWENLNQSNVRRMHTAVRLN
EVIVKKSRDAKLVLLNMPGPPRNRNGDENYMEFLEVLTEHLDRVMLVRGGGREVITIYS
Function
Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis. As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition. Involved in the regulation of dendritic spine formation and maturation.
Tissue Specificity Brain specific. Detected in neuronal cells.
KEGG Pathway
GABAergic sy.pse (hsa04727 )
Reactome Pathway
Cation-coupled Chloride cotransporters (R-HSA-426117 )

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Developmental and epileptic encephalopathy, 34 DISZRFFY Strong Autosomal recessive [1]
Malignant migrating partial seizures of infancy DISF2TRU Supportive Autosomal dominant [2]
Epilepsy, idiopathic generalized, susceptibility to, 14 DIS5VM21 Limited Autosomal dominant [3]
Infantile spasm DISZSKDG Limited Autosomal recessive [4]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
3 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Solute carrier family 12 member 5 (SLC12A5). [5]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Solute carrier family 12 member 5 (SLC12A5). [7]
Staurosporine DM0E9BR Investigative Staurosporine increases the activity of Solute carrier family 12 member 5 (SLC12A5). [8]
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1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Solute carrier family 12 member 5 (SLC12A5). [6]
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References

1 Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 2001 May;30(2):515-24. doi: 10.1016/s0896-6273(01)00297-5.
2 Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. Nat Commun. 2015 Sep 3;6:8038. doi: 10.1038/ncomms9038.
3 Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
4 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
5 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
6 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
7 Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4315-20. doi: 10.1073/pnas.1300959110. Epub 2013 Feb 25.
8 A thallium transport FLIPR-based assay for the identification of KCC2-positive modulators. J Biomol Screen. 2010 Feb;15(2):177-84. doi: 10.1177/1087057109355708. Epub 2010 Jan 19.