Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTX2G9M)

• DOT Name: Amiloride-sensitive sodium channel subunit delta (SCNN1D)
• Synonyms: Delta-NaCH; Epithelial Na(+) channel subunit delta; Delta-ENaC; ENaCD; Nonvoltage-gated sodium channel 1 subunit delta; SCNED
• Gene Name: SCNN1D
• Related Disease:
  Cystic fibrosis
  Epilepsy
  Gastroesophageal reflux disease
  Melanoma
  Pulmonary disease
  Temporal lobe epilepsy
• UniProt ID: SCNND_HUMAN
• Pfam ID: PF00858
• Sequence:
  MRAVLSQKTTPLPRYLWPGHLSGPRRLTWSWCSDHRTPTCRELGSPHPTPCTGPARGWPR
  RGGGPCGFTSAGHVLCGYPLCLLSGPIQGCGTGLGDSSMAFLSRTSPVAAASFQSRQEAR
  GSILLQSCQLPPQWLSTEAWTGEWKQPHGGALTSRSPGPVAPQRPCHLKGWQHRPTQHNA
  ACKQGQAAAQTPPRPGPPSAPPPPPKEGHQEGLVELPASFRELLTFFCTNATIHGAIRLV
  CSRGNRLKTTSWGLLSLGALVALCWQLGLLFERHWHRPVLMAVSVHSERKLLPLVTLCDG
  NPRRPSPVLRHLELLDEFARENIDSLYNVNLSKGRAALSATVPRHEPPFHLDREIRLQRL
  SHSGSRVRVGFRLCNSTGGDCFYRGYTSGVAAVQDWYHFHYVDILALLPAAWEDSHGSQD
  GHFVLSCSYDGLDCQARQFRTFHHPTYGSCYTVDGVWTAQRPGITHGVGLVLRVEQQPHL
  PLLSTLAGIRVMVHGRNHTPFLGHHSFSVRPGTEATISIREDEVHRLGSPYGHCTAGGEG
  VEVELLHNTSYTRQACLVSCFQQLMVETCSCGYYLHPLPAGAEYCSSARHPAWGHCFYRL
  YQDLETHRLPCTSRCPRPCRESAFKLSTGTSRWPSAKSAGWTLATLGEQGLPHQSHRQRS
  SLAKINIVYQELNYRSVEEAPVYSVPQLLSAMGSLCSLWFGASVLSLLELLELLLDASAL
  TLVLGGRRLRRAWFSWPRASPASGASSIKPEASQMPPPAGGTSDDPEPSGPHLPRVMLPG
  VLAGVSAEESWAGPQPLETLDT
• Function: Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception.
• Reactome Pathway:
  Sensory perception of salty taste (R-HSA-9730628)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[1]
Epilepsy	DISBB28L	Strong	Altered Expression	[2]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Altered Expression	[4]
Pulmonary disease	DIS6060I	Strong	Genetic Variation	[1]
Temporal lobe epilepsy	DISNOPXX	Strong	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Amiloride-sensitive sodium channel subunit delta (SCNN1D).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Amiloride-sensitive sodium channel subunit delta (SCNN1D).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Amiloride-sensitive sodium channel subunit delta (SCNN1D).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Amiloride-sensitive sodium channel subunit delta (SCNN1D).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Amiloride-sensitive sodium channel subunit delta (SCNN1D).	[7]

References

• [1] The Epithelial Sodium Channel Is a Modifier of the Long-Term Nonprogressive Phenotype Associated with F508del CFTR Mutations.Am J Respir Cell Mol Biol. 2017 Dec;57(6):711-720. doi: 10.1165/rcmb.2017-0166OC.
• [2] Elevated Expression of the Delta-Subunit of Epithelial Sodium Channel in Temporal Lobe Epilepsy Patients and Rat Model.J Mol Neurosci. 2015 Dec;57(4):510-8. doi: 10.1007/s12031-015-0630-6. Epub 2015 Aug 1.
• [3] Epithelial Na+ channel delta subunit is an acid sensor in the human oesophagus.Eur J Pharmacol. 2008 Dec 14;600(1-3):32-6. doi: 10.1016/j.ejphar.2008.10.022. Epub 2008 Oct 18.
• [4] Expression analysis of the epithelial Na+ channel delta subunit in human melanoma G-361 cells.Biochem Biophys Res Commun. 2008 Feb 8;366(2):489-92. doi: 10.1016/j.bbrc.2007.11.177. Epub 2007 Dec 10.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.