Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGSKLL8)

• DOT Name: Sodium channel protein type 9 subunit alpha (SCN9A)
• Synonyms: Neuroendocrine sodium channel; hNE-Na; Peripheral sodium channel 1; PN1; Sodium channel protein type IX subunit alpha; Voltage-gated sodium channel subunit alpha Nav1.7
• Gene Name: SCN9A
• Related Disease:
  Primary erythermalgia
  Channelopathy-associated congenital insensitivity to pain, autosomal recessive
  Generalized epilepsy with febrile seizures plus, type 7
  Paroxysmal extreme pain disorder
  Hereditary sensory and autonomic neuropathy type 2
  Obsolete sodium channelopathy-related small fiber neuropathy
  Epilepsy
• UniProt ID: SCN9A_HUMAN
• PDB ID: 5EK0 ; 6J8G ; 6J8H ; 6J8I ; 6J8J ; 6N4Q ; 6N4R ; 6NT3 ; 6NT4 ; 6VXO ; 6W6O ; 7K48 ; 7W9K ; 7W9L ; 7W9M ; 7W9P ; 7W9T ; 7XM9 ; 7XMF ; 7XMG ; 7XVE ; 7XVF ; 8F0P ; 8F0Q ; 8F0R ; 8F0S ; 8G1A ; 8I5B ; 8I5G ; 8I5X ; 8I5Y ; 8J4F ; 8S9B ; 8S9C ; 8THG ; 8THH
• Pfam ID: PF00520 ; PF06512 ; PF11933
• Sequence:
  MAMLPPPGPQSFVHFTKQSLALIEQRIAERKSKEPKEEKKDDDEEAPKPSSDLEAGKQLP
  FIYGDIPPGMVSEPLEDLDPYYADKKTFIVLNKGKTIFRFNATPALYMLSPFSPLRRISI
  KILVHSLFSMLIMCTILTNCIFMTMNNPPDWTKNVEYTFTGIYTFESLVKILARGFCVGE
  FTFLRDPWNWLDFVVIVFAYLTEFVNLGNVSALRTFRVLRALKTISVIPGLKTIVGALIQ
  SVKKLSDVMILTVFCLSVFALIGLQLFMGNLKHKCFRNSLENNETLESIMNTLESEEDFR
  KYFYYLEGSKDALLCGFSTDSGQCPEGYTCVKIGRNPDYGYTSFDTFSWAFLALFRLMTQ
  DYWENLYQQTLRAAGKTYMIFFVVVIFLGSFYLINLILAVVAMAYEEQNQANIEEAKQKE
  LEFQQMLDRLKKEQEEAEAIAAAAAEYTSIRRSRIMGLSESSSETSKLSSKSAKERRNRR
  KKKNQKKLSSGEEKGDAEKLSKSESEDSIRRKSFHLGVEGHRRAHEKRLSTPNQSPLSIR
  GSLFSARRSSRTSLFSFKGRGRDIGSETEFADDEHSIFGDNESRRGSLFVPHRPQERRSS
  NISQASRSPPMLPVNGKMHSAVDCNGVVSLVDGRSALMLPNGQLLPEVIIDKATSDDSGT
  TNQIHKKRRCSSYLLSEDMLNDPNLRQRAMSRASILTNTVEELEESRQKCPPWWYRFAHK
  FLIWNCSPYWIKFKKCIYFIVMDPFVDLAITICIVLNTLFMAMEHHPMTEEFKNVLAIGN
  LVFTGIFAAEMVLKLIAMDPYEYFQVGWNIFDSLIVTLSLVELFLADVEGLSVLRSFRLL
  RVFKLAKSWPTLNMLIKIIGNSVGALGNLTLVLAIIVFIFAVVGMQLFGKSYKECVCKIN
  DDCTLPRWHMNDFFHSFLIVFRVLCGEWIETMWDCMEVAGQAMCLIVYMMVMVIGNLVVL
  NLFLALLLSSFSSDNLTAIEEDPDANNLQIAVTRIKKGINYVKQTLREFILKAFSKKPKI
  SREIRQAEDLNTKKENYISNHTLAEMSKGHNFLKEKDKISGFGSSVDKHLMEDSDGQSFI
  HNPSLTVTVPIAPGESDLENMNAEELSSDSDSEYSKVRLNRSSSSECSTVDNPLPGEGEE
  AEAEPMNSDEPEACFTDGCVWRFSCCQVNIESGKGKIWWNIRKTCYKIVEHSWFESFIVL
  MILLSSGALAFEDIYIERKKTIKIILEYADKIFTYIFILEMLLKWIAYGYKTYFTNAWCW
  LDFLIVDVSLVTLVANTLGYSDLGPIKSLRTLRALRPLRALSRFEGMRVVVNALIGAIPS
  IMNVLLVCLIFWLIFSIMGVNLFAGKFYECINTTDGSRFPASQVPNRSECFALMNVSQNV
  RWKNLKVNFDNVGLGYLSLLQVATFKGWTIIMYAAVDSVNVDKQPKYEYSLYMYIYFVVF
  IIFGSFFTLNLFIGVIIDNFNQQKKKLGGQDIFMTEEQKKYYNAMKKLGSKKPQKPIPRP
  GNKIQGCIFDLVTNQAFDISIMVLICLNMVTMMVEKEGQSQHMTEVLYWINVVFIILFTG
  ECVLKLISLRHYYFTVGWNIFDFVVVIISIVGMFLADLIETYFVSPTLFRVIRLARIGRI
  LRLVKGAKGIRTLLFALMMSLPALFNIGLLLFLVMFIYAIFGMSNFAYVKKEDGINDMFN
  FETFGNSMICLFQITTSAGWDGLLAPILNSKPPDCDPKKVHPGSSVEGDCGNPSVGIFYF
  VSYIIISFLVVVNMYIAVILENFSVATEESTEPLSEDDFEMFYEVWEKFDPDATQFIEFS
  KLSDFAAALDPPLLIAKPNKVQLIAMDLPMVSGDRIHCLDILFAFTKRVLGESGEMDSLR
  SQMEERFMSANPSKVSYEPITTTLKRKQEDVSATVIQRAYRRYRLRQNVKNISSIYIKDG
  DRDDDLLNKKDMAFDNVNENSSPEKTDATSSTTSPPSYDSVTKPDKEKYEQDRTEKEDKG
  KDSKESKK
• 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, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-sensitive Na(+) channel isoform. Plays a role in pain mechanisms, especially in the development of inflammatory pain.
• Tissue Specificity: Expressed strongly in dorsal root ganglion, with only minor levels elsewhere in the body, smooth muscle cells, MTC cell line and C-cell carcinoma. Also expressed in vagus nerves within the head and neck region . Isoform 1 is expressed preferentially in the central and peripheral nervous system. Isoform 2 is expressed preferentially in the dorsal root ganglion.
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary erythermalgia	DISRR1LN	Definitive	Autosomal dominant	[1]
Channelopathy-associated congenital insensitivity to pain, autosomal recessive	DISJ1NV4	Strong	Autosomal recessive	[2]
Generalized epilepsy with febrile seizures plus, type 7	DIS2C0N3	Strong	Autosomal dominant	[3]
Paroxysmal extreme pain disorder	DISNHO6B	Strong	Autosomal dominant	[4]
Hereditary sensory and autonomic neuropathy type 2	DIS4TP1G	Supportive	Autosomal recessive	[5]
Obsolete sodium channelopathy-related small fiber neuropathy	DISQL23S	Supportive	Autosomal dominant	[6]
Epilepsy	DISBB28L	Limited	Autosomal dominant	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Sodium channel protein type 9 subunit alpha (SCN9A) affects the response to substance of Carbamazepine.	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[14]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the activity of Sodium channel protein type 9 subunit alpha (SCN9A).	[15]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[16]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[16]
Tetrodotoxin	DMWMPRG	Approved	Tetrodotoxin decreases the activity of Sodium channel protein type 9 subunit alpha (SCN9A).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[23]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Sodium channel protein type 9 subunit alpha (SCN9A).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sodium channel protein type 9 subunit alpha (SCN9A).	[21]

References

• [1] Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004 Mar;41(3):171-4. doi: 10.1136/jmg.2003.012153.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome. PLoS Genet. 2009 Sep;5(9):e1000649. doi: 10.1371/journal.pgen.1000649. Epub 2009 Sep 18.
• [4] SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006 Dec 7;52(5):767-74. doi: 10.1016/j.neuron.2006.10.006.
• [5] Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation. Neurology. 2013 Apr 30;80(18):1641-9. doi: 10.1212/WNL.0b013e3182904fdd. Epub 2013 Apr 17.
• [6] Gain of function Na1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012 Jan;71(1):26-39. doi: 10.1002/ana.22485. Epub 2011 Jun 22.
• [7] Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J. 1995 Mar 15;14(6):1084-90. doi: 10.1002/j.1460-2075.1995.tb07091.x.
• [8] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] 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.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Na(v1.6) voltage-dependent sodium channel. Am J Physiol Cell Physiol. 2007 Aug;293(2):C783-9.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [20] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [21] 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.
• [22] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [23] 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.
• [24] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.