Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY3QMBN)

• DOT Name: Sodium/potassium/calcium exchanger 1 (SLC24A1)
• Synonyms: Na(+)/K(+)/Ca(2+)-exchange protein 1; Retinal rod Na-Ca+K exchanger; Solute carrier family 24 member 1
• Gene Name: SLC24A1
• Related Disease:
  Congenital stationary night blindness 1D
  Congenital stationary night blindness
• UniProt ID: NCKX1_HUMAN
• Pfam ID: PF01699
• Sequence:
  MGKLIRMGPQERWLLRTKRLHWSRLLFLLGMLIIGSTYQHLRRPRGLSSLWAAVSSHQPI
  KLASRDLSSEEMMMMSSSPSKPSSEMGGKMLVPQASVGSDEATLSMTVENIPSMPKRTAK
  MIPTTTKNNYSPTAAGTERRKEDTPTSSRTLTYYTSTSSRQIVKKYTPTPRGEMKSYSPT
  QVREKVKYTPSPRGRRVGTYVPSTFMTMETSHAITPRTTVKDSDITATYKILETNSLKRI
  MEETTPTTLKGMFDSTPTFLTHEVEANVLTSPRSVMEKNNLFPPRRVESNSSAHPWGLVG
  KSNPKTPQGTVLLHTPATSEGQVTISTMTGSSPAETKAFTAAWSLRNPSPRTSVSAIKTA
  PAIVWRLAKKPSTAPSTSTTPTVRAKLTMQVHHCVVVKPTPAMLTTPSPSLTTALLPEEL
  SPSPSVLPPSLPDLHPKGEYPPDLFSVEERRQGWVVLHVFGMMYVFVALAIVCDEYFVPA
  LGVITDKLQISEDVAGATFMAAGGSAPELFTSLIGVFISHSNVGIGTIVGSAVFNILFVI
  GTCSLFSREILNLTWWPLFRDVSFYILDLIMLILFFLDSLIAWWESLLLLLAYAFYVFTM
  KWNKHIEVWVKEQLSRRPVAKVMALEDLSKPGDGAIAVDELQDNKKLKLPSLLTRGSSST
  SLHNSTIRSTIYQLMLHSLDPLREVRLAKEKEEESLNQGARAQPQAKAESKPEEEEPAKL
  PAVTVTPAPVPDIKGDQKENPGGQEDVAEAESTGEMPGEEGETAGEGETEEKSGGETQPE
  GEGETETQGKGEECEDENEAEGKGDNEGEDEGEIHAEDGEMKGNEGETESQELSAENHGE
  AKNDEKGVEDGGGSDGGDSEEEEEEEEEQEEEEEEEEQEEEEEEEEEEEEKGNEEPLSLD
  WPETRQKQAIYLFLLPIVFPLWLTVPDVRRQESRKFFVFTFLGSIMWIAMFSYLMVWWAH
  QVGETIGISEEIMGLTILAAGTSIPDLITSVIVARKGLGDMAVSSSVGSNIFDITVGLPV
  PWLLFSLINGLQPVPVSSNGLFCAIVLLFLMLLFVISSIASCKWRMNKILGFTMFLLYFV
  FLIISVMLEDRIISCPVSV
• Function: Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+). Critical component of the visual transduction cascade, controlling the calcium concentration of outer segments during light and darkness. Light causes a rapid lowering of cytosolic free calcium in the outer segment of both retinal rod and cone photoreceptors and the light-induced lowering of calcium is caused by extrusion via this protein which plays a key role in the process of light adaptation.
• Tissue Specificity: Expressed in the retina, particularly in the inner segment, outer and inner nuclear layers, and ganglion cell layer.
• KEGG Pathway: Phototransduction (hsa04744)
• Reactome Pathway:
  Sodium/Calcium exchangers (R-HSA-425561)
  Defective SLC24A1 causes congenital stationary night blindness 1D (CSNB1D) (R-HSA-5619077)
  Activation of the phototransduction cascade (R-HSA-2485179)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital stationary night blindness 1D	DISE54LW	Strong	Autosomal recessive	[1]
Congenital stationary night blindness	DISX0CWK	Supportive	Autosomal dominant	[2]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sodium/potassium/calcium exchanger 1 (SLC24A1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium/potassium/calcium exchanger 1 (SLC24A1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium/potassium/calcium exchanger 1 (SLC24A1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium/potassium/calcium exchanger 1 (SLC24A1).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium/potassium/calcium exchanger 1 (SLC24A1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sodium/potassium/calcium exchanger 1 (SLC24A1).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium/potassium/calcium exchanger 1 (SLC24A1).	[9]

References

• [1] Mutated alleles of the rod and cone Na-Ca+K-exchanger genes in patients with retinal diseases. Invest Ophthalmol Vis Sci. 2002 Jun;43(6):1971-9.
• [2] A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness. Am J Hum Genet. 2010 Oct 8;87(4):523-31. doi: 10.1016/j.ajhg.2010.08.013. Epub 2010 Sep 16.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [9] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.