Details of Drug Off-Target (DOT)

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

• DOT Name: Sodium/hydrogen exchanger 4 (SLC9A4)
• Synonyms: Na(+)/H(+) exchanger 4; NHE-4; Solute carrier family 9 member 4
• Gene Name: SLC9A4
• UniProt ID: SL9A4_HUMAN
• Pfam ID: PF00999 ; PF16644
• Sequence:
  MALQMFVTYSPWNCLLLLVALECSEASSDLNESANSTAQYASNAWFAAASSEPEEGISVF
  ELDYDYVQIPYEVTLWILLASLAKIGFHLYHRLPGLMPESCLLILVGALVGGIIFGTDHK
  SPPVMDSSIYFLYLLPPIVLEGGYFMPTRPFFENIGSILWWAVLGALINALGIGLSLYLI
  CQVKAFGLGDVNLLQNLLFGSLISAVDPVAVLAVFEEARVNEQLYMMIFGEALLNDGITV
  VLYNMLIAFTKMHKFEDIETVDILAGCARFIVVGLGGVLFGIVFGFISAFITRFTQNISA
  IEPLIVFMFSYLSYLAAETLYLSGILAITACAVTMKKYVEENVSQTSYTTIKYFMKMLSS
  VSETLIFIFMGVSTVGKNHEWNWAFICFTLAFCQIWRAISVFALFYISNQFRTFPFSIKD
  QCIIFYSGVRGAGSFSLAFLLPLSLFPRKKMFVTATLVVIYFTVFIQGITVGPLVRYLDV
  KKTNKKESINEELHIRLMDHLKAGIEDVCGHWSHYQVRDKFKKFDHRYLRKILIRKNLPK
  SSIVSLYKKLEMKQAIEMVETGILSSTAFSIPHQAQRIQGIKRLSPEDVESIRDILTSNM
  YQVRQRTLSYNKYNLKPQTSEKQAKEILIRRQNTLRESMRKGHSLPWGKPAGTKNIRYLS
  YPYGNPQSAGRDTRAAGFSDDDSSDPGSPSITFSACSRIGSLQKQEAQEIIPMKSLHRGR
  KAFSFGYQRNTSQEEYLGGVRRVALRPKPLFHAVDEEGESGGESEGKASLVEVRSRWTAD
  HGHGRDHHRSHSPLLQKK
• Function: Electroneutral antiporter that exchanges sodium for protons or ammonium ions at the basolateral membrane of epithelia to regulate cell volume and intracellular pH upon hypertonic conditions. As part of transcellular ammonia transport in renal tubules, mediates basolateral ammonium extrusion in the medullary thick ascending limb, regulating the corticopapillary ammonium gradient and overall renal acid excretion. Mediates sodium:proton exchange in gastric parietal cells secondary to cAMP-dependent acid secretion and hyperosmolarity. Possibly coupled to chloride:bicarbonate antiporter, enables loading of parietal cells with sodium and chloride ions to maintain cell volume and normal gastric acid secretion. Functions as a sodium sensor in neurons of organum vasculosum of the lamina terminalis where it regulates water intake in response to increased sodium concentration in body fluids.
• KEGG Pathway: Gastric acid secretion (hsa04971)
• Reactome Pathway: Sodium/Proton exchangers (R-HSA-425986)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Sodium/hydrogen exchanger 4 (SLC9A4) affects the uptake of 3-iodothyronamine.	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Sodium/hydrogen exchanger 4 (SLC9A4).	[1]

2 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 Sodium/hydrogen exchanger 4 (SLC9A4).	[2]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Sodium/hydrogen exchanger 4 (SLC9A4).	[3]

References

• [1] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [2] 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.
• [3] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [4] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.