Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP6227G)

• DOT Name: Voltage-dependent calcium channel gamma-8 subunit (CACNG8)
• Synonyms: Neuronal voltage-gated calcium channel gamma-8 subunit; Transmembrane AMPAR regulatory protein gamma-8; TARP gamma-8
• Gene Name: CACNG8
• Related Disease:
  Schizophrenia
  Cardiomyopathy
• UniProt ID: CCG8_HUMAN
• Pfam ID: PF00822
• Sequence:
  MESLKRWNEERGLWCEKGVQVLLTTVGAFAAFGLMTIAISTDYWLYTRALICNTTNLTAG
  GDDGTPHRGGGGASEKKDPGGLTHSGLWRICCLEGLKRGVCVKINHFPEDTDYDHDSAEY
  LLRVVRASSIFPILSAILLLLGGVCVAASRVYKSKRNIILGAGILFVAAGLSNIIGVIVY
  ISANAGEPGPKRDEEKKNHYSYGWSFYFGGLSFILAEVIGVLAVNIYIERSREAHCQSRS
  DLLKAGGGAGGSGGSGPSAILRLPSYRFRYRRRSRSSSRSSEPSPSRDASPGGPGGPGFA
  STDISMYTLSRDPSKGSVAAGLAGAGGGGGGAVGAFGGAAGGAGGGGGGGGGAGAERDRG
  GASGFLTLHNAFPKEAGGGVTVTVTGPPAPPAPAPPAPSAPAPGTLAKEAAASNTNTLNR
  KTTPV
• Function: Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit. Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits.
• Tissue Specificity: Detected in heart left ventricle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Oxytocin sig.ling pathway (hsa04921)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Phase 2 - plateau phase (R-HSA-5576893)
  LGI-ADAM interactions (R-HSA-5682910)
  Trafficking of AMPA receptors (R-HSA-399719)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	moderate	Biomarker	[1]
Cardiomyopathy	DISUPZRG	Limited	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 Voltage-dependent calcium channel gamma-8 subunit (CACNG8).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Voltage-dependent calcium channel gamma-8 subunit (CACNG8).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Voltage-dependent calcium channel gamma-8 subunit (CACNG8).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Voltage-dependent calcium channel gamma-8 subunit (CACNG8).	[5]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Voltage-dependent calcium channel gamma-8 subunit (CACNG8).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Voltage-dependent calcium channel gamma-8 subunit (CACNG8).	[7]

References

• [1] Evaluation of voltage-dependent calcium channel gene families identified several novel potential susceptible genes to schizophrenia.Sci Rep. 2016 Apr 22;6:24914. doi: 10.1038/srep24914.
• [2] Patients with Dilated Cardiomyopathy and Sustained Monomorphic Ventricular Tachycardia Show Up-Regulation of KCNN3 and KCNJ2 Genes and CACNG8-Linked Left Ventricular Dysfunction.PLoS One. 2015 Dec 28;10(12):e0145518. doi: 10.1371/journal.pone.0145518. eCollection 2015.
• [3] 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.
• [4] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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.