Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVYNX7N)

• DOT Name: Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4)
• Synonyms: Voltage-gated calcium channel subunit alpha-2/delta-4
• Gene Name: CACNA2D4
• Related Disease:
  Inherited retinal dystrophy
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Bronchopulmonary dysplasia
  Cone dystrophy
  Cone-rod dystrophy 2
  HIV infectious disease
  Mental disorder
  Retinal cone dystrophy 4
  Night blindness
  Cone-rod dystrophy
• UniProt ID: CA2D4_HUMAN
• Pfam ID: PF08473 ; PF13768 ; PF08399
• Sequence:
  MVCGCSALLPLPNPRPTMPATPNFLANPSSSSRWIPLQPMPVAWAFVQKTSALLWLLLLG
  TSLSPAWGQAKIPLETVKLWADTFGGDLYNTVTKYSGSLLLQKKYKDVESSLKIEEVDGL
  ELVRKFSEDMENMLRRKVEAVQNLVEAAEEADLNHEFNESLVFDYYNSVLINERDEKGNF
  VELGAEFLLESNAHFSNLPVNTSISSVQLPTNVYNKDPDILNGVYMSEALNAVFVENFQR
  DPTLTWQYFGSATGFFRIYPGIKWTPDENGVITFDCRNRGWYIQAATSPKDIVILVDVSG
  SMKGLRMTIAKHTITTILDTLGENDFINIIAYNDYVHYIEPCFKGILVQADRDNREHFKL
  LVEELMVKGVGVVDQALREAFQILKQFQEAKQGSLCNQAIMLISDGAVEDYEPVFEKYNW
  PDCKVRVFTYLIGREVSFADRMKWIACNNKGYYTQISTLADTQENVMEYLHVLSRPMVIN
  HDHDIIWTEAYMDSKLLSSQAQSLTLLTTVAMPVFSKKNETRSHGILLGVVGSDVALREL
  MKLAPRYKLGVHGYAFLNTNNGYILSHPDLRPLYREGKKLKPKPNYNSVDLSEVEWEDQA
  ESLRTAMINRETGTLSMDVKVPMDKGKRVLFLTNDYFFTDISDTPFSLGVVLSRGHGEYI
  LLGNTSVEEGLHDLLHPDLALAGDWIYCITDIDPDHRKLSQLEAMIRFLTRKDPDLECDE
  ELVREVLFDAVVTAPMEAYWTALALNMSEESEHVVDMAFLGTRAGLLRSSLFVGSEKVSD
  RKFLTPEDEASVFTLDRFPLWYRQASEHPAGSFVFNLRWAEGPESAGEPMVVTASTAVAV
  TVDKRTAIAAAAGVQMKLEFLQRKFWAATRQCSTVDGPCTQSCEDSDLDCFVIDNNGFIL
  ISKRSRETGRFLGEVDGAVLTQLLSMGVFSQVTMYDYQAMCKPSSHHHSAAQPLVSPISA
  FLTATRWLLQELVLFLLEWSVWGSWYDRGAEAKSVFHHSHKHKKQDPLQPCDTEYPVFVY
  QPAIREANGIVECGPCQKVFVVQQIPNSNLLLLVTDPTCDCSIFPPVLQEATEVKYNASV
  KCDRMRSQKLRRRPDSCHAFHPEENAQDCGGASDTSASPPLLLLPVCAWGLLPQLLR
• Function: The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
• Tissue Specificity: Predominantly expressed in certain types of endocrine cells. Present in the Paneth cells of the small intestine. Also present in the erythroblasts in the fetal liver, in the cells of the zona reticularis of the adrenal gland and in the basophils of the pituitary. Present at low level in some brain regions such as the cerebellum (at protein level).
• 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)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	Autosomal recessive	[1]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[2]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[3]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Genetic Variation	[4]
Cone dystrophy	DIS7SAZZ	Strong	Genetic Variation	[5]
Cone-rod dystrophy 2	DISX2RWY	Strong	GermlineCausalMutation	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[4]
Retinal cone dystrophy 4	DISKD4ND	Strong	Autosomal recessive	[5]
Night blindness	DIS335K9	moderate	Genetic Variation	[5]
Cone-rod dystrophy	DISY9RWN	Supportive	Autosomal dominant	[5]

4 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 subunit alpha-2/delta-4 (CACNA2D4).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[10]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-4 (CACNA2D4).	[17]

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] circRNA/lncRNA-miRNA-mRNA Network in Oxidized, Low-Density, Lipoprotein-Induced Foam Cells.DNA Cell Biol. 2019 Dec;38(12):1499-1511. doi: 10.1089/dna.2019.4865.
• [3] Whole-exome sequencing in familial atrial fibrillation.Eur Heart J. 2014 Sep 21;35(36):2477-83. doi: 10.1093/eurheartj/ehu156. Epub 2014 Apr 11.
• [4] Identification of a CACNA2D4 deletion in late onset bipolar disorder patients and implications for the involvement of voltage-dependent calcium channels in psychiatric disorders.Am J Med Genet B Neuropsychiatr Genet. 2012 Jun;159B(4):465-75. doi: 10.1002/ajmg.b.32053. Epub 2012 Apr 9.
• [5] Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy. Am J Hum Genet. 2006 Nov;79(5):973-7. doi: 10.1086/508944. Epub 2006 Sep 27.
• [6] Purified recombinant CD4 inhibits HIV-1 infection of peripheral blood macrophages.Pathol Biol (Paris). 1991 Oct;39(8):754-8.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [12] 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.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.