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
• 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]

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]

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]

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.