Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT8KA0F)

• DOT Name: Mitochondrial sodium/calcium exchanger protein (SLC8B1)
• Synonyms: Na(+)/K(+)/Ca(2+)-exchange protein 6; Sodium/calcium exchanger protein, mitochondrial; Sodium/potassium/calcium exchanger 6; Solute carrier family 24 member 6; Solute carrier family 8 member B1
• Gene Name: SLC8B1
• UniProt ID: NCLX_HUMAN
• Pfam ID: PF01699
• Sequence:
  MAGRRLNLRWALSVLCVLLMAETVSGTRGSSTGAHISPQFPASGVNQTPVVDCRKVCGLN
  VSDRCDFIRTNPDCHSDGGYLDYLEGIFCHFPPSLLPLAVTLYVSWLLYLFLILGVTAAK
  FFCPNLSAISTTLKLSHNVAGVTFLAFGNGAPDIFSALVAFSDPHTAGLALGALFGAGVL
  VTTVVAGGITILHPFMAASRPFFRDIVFYMVAVFLTFLMLFRGRVTLAWALGYLGLYVFY
  VVTVILCTWIYQRQRRGSLFCPMPVTPEILSDSEEDRVSSNTNSYDYGDEYRPLFFYQET
  TAQILVRALNPLDYMKWRRKSAYWKALKVFKLPVEFLLLLTVPVVDPDKDDQNWKRPLNC
  LHLVISPLVVVLTLQSGTYGVYEIGGLVPVWVVVVIAGTALASVTFFATSDSQPPRLHWL
  FAFLGFLTSALWINAAATEVVNILRSLGVVFRLSNTVLGLTLLAWGNSIGDAFSDFTLAR
  QGYPRMAFSACFGGIIFNILVGVGLGCLLQISRSHTEVKLEPDGLLVWVLAGALGLSLVF
  SLVSVPLQCFQLSRVYGFCLLLFYLNFLVVALLTEFGVIHLKSM
• Function: Mitochondrial sodium/calcium antiporter that mediates sodium-dependent calcium efflux from mitochondrion, by mediating the exchange of 3 sodium ions per 1 calcium ion. Plays a central role in mitochondrial calcium homeostasis by mediating mitochondrial calcium extrusion: calcium efflux is essential for mitochondrial function and cell survival, notably in cardiomyocytes. Regulates rates of glucose-dependent insulin secretion in pancreatic beta-cells during the first phase of insulin secretion: acts by mediating efflux of calcium from mitochondrion, thereby affecting cytoplasmic calcium responses. Required for store-operated Ca(2+) entry (SOCE) and Ca(2+) release-activated Ca(2+) (CRAC) channel regulation: sodium transport by SLC8B1 leads to promote calcium-shuttling that modulates mitochondrial redox status, thereby regulating SOCE activity. Involved in B-lymphocyte chemotaxis. Able to transport Ca(2+) in exchange of either Li(+) or Na(+), explaining how Li(+) catalyzes Ca(2+) exchange. In contrast to other members of the family its function is independent of K(+).
• Tissue Specificity: Present in pancreatic beta-cells (at protein level).
• Reactome Pathway:
  Mitochondrial calcium ion transport (R-HSA-8949215)
  Sodium/Calcium exchangers (R-HSA-425561)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[3]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[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 decreases the methylation of Mitochondrial sodium/calcium exchanger protein (SLC8B1).	[5]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] 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.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [5] 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.
• [6] 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.
• [7] Genome-wide gene expression profiling of low-dose, long-term exposure of human osteosarcoma cells to bisphenol A and its analogs bisphenols AF and S. Toxicol In Vitro. 2015 Aug;29(5):1060-9.
• [8] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.