Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4C2LCB)

• DOT Name: Sodium channel protein type 3 subunit alpha (SCN3A)
• Synonyms: Sodium channel protein brain III subunit alpha; Sodium channel protein type III subunit alpha; Voltage-gated sodium channel subtype III; Voltage-gated sodium channel subunit alpha Nav1.3
• Gene Name: SCN3A
• Related Disease:
  Infantile spasm
  Developmental and epileptic encephalopathy, 62
  Epilepsy, familial focal, with variable foci 4
  Undetermined early-onset epileptic encephalopathy
• UniProt ID: SCN3A_HUMAN
• PDB ID: 7W77; 7W7F
• Pfam ID: PF00520 ; PF06512 ; PF11933
• Sequence:
  MAQALLVPPGPESFRLFTRESLAAIEKRAAEEKAKKPKKEQDNDDENKPKPNSDLEAGKN
  LPFIYGDIPPEMVSEPLEDLDPYYINKKTFIVMNKGKAIFRFSATSALYILTPLNPVRKI
  AIKILVHSLFSMLIMCTILTNCVFMTLSNPPDWTKNVEYTFTGIYTFESLIKILARGFCL
  EDFTFLRDPWNWLDFSVIVMAYVTEFVSLGNVSALRTFRVLRALKTISVIPGLKTIVGAL
  IQSVKKLSDVMILTVFCLSVFALIGLQLFMGNLRNKCLQWPPSDSAFETNTTSYFNGTMD
  SNGTFVNVTMSTFNWKDYIGDDSHFYVLDGQKDPLLCGNGSDAGQCPEGYICVKAGRNPN
  YGYTSFDTFSWAFLSLFRLMTQDYWENLYQLTLRAAGKTYMIFFVLVIFLGSFYLVNLIL
  AVVAMAYEEQNQATLEEAEQKEAEFQQMLEQLKKQQEEAQAVAAASAASRDFSGIGGLGE
  LLESSSEASKLSSKSAKEWRNRRKKRRQREHLEGNNKGERDSFPKSESEDSVKRSSFLFS
  MDGNRLTSDKKFCSPHQSLLSIRGSLFSPRRNSKTSIFSFRGRAKDVGSENDFADDEHST
  FEDSESRRDSLFVPHRHGERRNSNVSQASMSSRMVPGLPANGKMHSTVDCNGVVSLVGGP
  SALTSPTGQLPPEGTTTETEVRKRRLSSYQISMEMLEDSSGRQRAVSIASILTNTMEELE
  ESRQKCPPCWYRFANVFLIWDCCDAWLKVKHLVNLIVMDPFVDLAITICIVLNTLFMAME
  HYPMTEQFSSVLTVGNLVFTGIFTAEMVLKIIAMDPYYYFQEGWNIFDGIIVSLSLMELG
  LSNVEGLSVLRSFRLLRVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVG
  MQLFGKSYKECVCKINDDCTLPRWHMNDFFHSFLIVFRVLCGEWIETMWDCMEVAGQTMC
  LIVFMLVMVIGNLVVLNLFLALLLSSFSSDNLAATDDDNEMNNLQIAVGRMQKGIDYVKN
  KMRECFQKAFFRKPKVIEIHEGNKIDSCMSNNTGIEISKELNYLRDGNGTTSGVGTGSSV
  EKYVIDENDYMSFINNPSLTVTVPIAVGESDFENLNTEEFSSESELEESKEKLNATSSSE
  GSTVDVVLPREGEQAETEPEEDLKPEACFTEGCIKKFPFCQVSTEEGKGKIWWNLRKTCY
  SIVEHNWFETFIVFMILLSSGALAFEDIYIEQRKTIKTMLEYADKVFTYIFILEMLLKWV
  AYGFQTYFTNAWCWLDFLIVDVSLVSLVANALGYSELGAIKSLRTLRALRPLRALSRFEG
  MRVVVNALVGAIPSIMNVLLVCLIFWLIFSIMGVNLFAGKFYHCVNMTTGNMFDISDVNN
  LSDCQALGKQARWKNVKVNFDNVGAGYLALLQVATFKGWMDIMYAAVDSRDVKLQPVYEE
  NLYMYLYFVIFIIFGSFFTLNLFIGVIIDNFNQQKKKFGGQDIFMTEEQKKYYNAMKKLG
  SKKPQKPIPRPANKFQGMVFDFVTRQVFDISIMILICLNMVTMMVETDDQGKYMTLVLSR
  INLVFIVLFTGEFVLKLVSLRHYYFTIGWNIFDFVVVILSIVGMFLAEMIEKYFVSPTLF
  RVIRLARIGRILRLIKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGMSNFAYV
  KKEAGIDDMFNFETFGNSMICLFQITTSAGWDGLLAPILNSAPPDCDPDTIHPGSSVKGD
  CGNPSVGIFFFVSYIIISFLVVVNMYIAVILENFSVATEESAEPLSEDDFEMFYEVWEKF
  DPDATQFIEFSKLSDFAAALDPPLLIAKPNKVQLIAMDLPMVSGDRIHCLDILFAFTKRV
  LGESGEMDALRIQMEDRFMASNPSKVSYEPITTTLKRKQEEVSAAIIQRNFRCYLLKQRL
  KNISSNYNKEAIKGRIDLPIKQDMIIDKLNGNSTPEKTDGSSSTTSPPSYDSVTKPDKEK
  FEKDKPEKESKGKEVRENQK
• Function: Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. May contribute to the regulation of serotonin/5-hydroxytryptamine release by enterochromaffin cells. In pancreatic endocrine cells, required for both glucagon and glucose-induced insulin secretion.
• Tissue Specificity: Expressed in enterochromaffin cells in both colon and small bowel (at protein level).
• KEGG Pathway: Taste transduction (hsa04742)
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)
  Interaction between L1 and Ankyrins (R-HSA-445095)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal dominant	[1]
Developmental and epileptic encephalopathy, 62	DISO2G9R	Strong	Autosomal dominant	[2]
Epilepsy, familial focal, with variable foci 4	DISYBQ1A	Strong	Autosomal dominant	[3]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Sodium channel protein type 3 subunit alpha (SCN3A).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sodium channel protein type 3 subunit alpha (SCN3A).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Sodium channel protein type 3 subunit alpha (SCN3A).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sodium channel protein type 3 subunit alpha (SCN3A).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium channel protein type 3 subunit alpha (SCN3A).	[10]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Phenytoin	DMNOKBV	Approved	Phenytoin affects the binding of Sodium channel protein type 3 subunit alpha (SCN3A).	[7]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016 Sep;18(9):898-905. doi: 10.1038/gim.2015.186. Epub 2016 Jan 21.
• [3] Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci Lett. 2008 Mar 5;433(1):65-70. doi: 10.1016/j.neulet.2007.12.064. Epub 2008 Jan 11.
• [4] Mutations in SCN3A cause early infantile epileptic encephalopathy. Ann Neurol. 2018 Apr;83(4):703-717. doi: 10.1002/ana.25188. Epub 2018 Mar 30.
• [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] Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J Biol Chem. 2018 Oct 26;293(43):16546-16558. doi: 10.1074/jbc.RA118.004929. Epub 2018 Sep 14.
• [7] An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin. Epilepsy Res. 2005 May;64(3):77-84. doi: 10.1016/j.eplepsyres.2005.03.003.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.