Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLJTZ0E)

• DOT Name: Sodium/potassium/calcium exchanger 4 (SLC24A4)
• Synonyms: Na(+)/K(+)/Ca(2+)-exchange protein 4; Solute carrier family 24 member 4
• Gene Name: SLC24A4
• Related Disease:
  Amelogenesis imperfecta hypomaturation type 2A5
  Amelogenesis imperfecta type 2
  Amelogenesis imperfecta, type 3A
• UniProt ID: NCKX4_HUMAN
• Pfam ID: PF01699
• Sequence:
  MALRGTLRPLKVRRRREMLPQQVGFVCAVLALVCCASGLFGSLGHKTASASKRVLPDTWR
  NRKLMAPVNGTQTAKNCTDPAIHEFPTDLFSNKERQHGAVLLHILGALYMFYALAIVCDD
  FFVPSLEKICERLHLSEDVAGATFMAAGSSTPELFASVIGVFITHGDVGVGTIVGSAVFN
  ILCIIGVCGLFAGQVVRLTWWAVCRDSVYYTISVIVLIVFIYDEQIVWWEGLVLIILYVF
  YILIMKYNVKMQAFFTVKQKSIANGNPVNSELEAGNDFYDGSYDDPSVPLLGQVKEKPQY
  GKNPVVMVDEIMSSSPPKFTFPEAGLRIMITNKFGPRTRLRMASRIIINERQRLINSANG
  VSSKPLQNGRHENIENGNVPVENPEDPQQNQEQQPPPQPPPPEPEPVEADFLSPFSVPEA
  RGDKVKWVFTWPLIFLLCVTIPNCSKPRWEKFFMVTFITATLWIAVFSYIMVWLVTIIGY
  TLGIPDVIMGITFLAAGTSVPDCMASLIVARQGLGDMAVSNTIGSNVFDILVGLGVPWGL
  QTMVVNYGSTVKINSRGLVYSVVLLLGSVALTVLGIHLNKWRLDRKLGVYVLVLYAIFLC
  FSIMIEFNVFTFVNLPMCREDD
• Function: Calcium, potassium:sodium antiporter that transports 1 Ca(2+) and 1 K(+) in exchange for 4 Na(+). Controls the rapid response termination and proper regulation of adaptation in olfactory sensory neurons (OSNs) which subsequently influences how odor information is encoded and perceived. May play a role in calcium transport during amelogenesis.
• Tissue Specificity: Expressed abundantly in all regions of the brain, aorta, lung and thymus . Expressed at lower levels in the stomach and intestine .
• KEGG Pathway: Olfactory transduction (hsa04740)
• Reactome Pathway:
  Defective SLC24A4 causes hypomineralized amelogenesis imperfecta (AI) (R-HSA-5619055)
  Sodium/Calcium exchangers (R-HSA-425561)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amelogenesis imperfecta hypomaturation type 2A5	DIS1554S	Strong	Autosomal recessive	[1]
Amelogenesis imperfecta type 2	DISX8NN4	Supportive	Autosomal recessive	[2]
Amelogenesis imperfecta, type 3A	DISP3OJG	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sodium/potassium/calcium exchanger 4 (SLC24A4).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Sodium/potassium/calcium exchanger 4 (SLC24A4).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sodium/potassium/calcium exchanger 4 (SLC24A4).	[6]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium/potassium/calcium exchanger 4 (SLC24A4).	[4]

References

• [1] Identification of mutations in SLC24A4, encoding a potassium-dependent sodium/calcium exchanger, as a cause of amelogenesis imperfecta. Am J Hum Genet. 2013 Feb 7;92(2):307-12. doi: 10.1016/j.ajhg.2013.01.003. Epub 2013 Jan 31.
• [2] STIM1 and SLC24A4 Are Critical for Enamel Maturation. J Dent Res. 2014 Jul;93(7 Suppl):94S-100S. doi: 10.1177/0022034514527971. Epub 2014 Mar 12.
• [3] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [6] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.