Details of Drug Off-Target (DOT)

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

• DOT Name: Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2)
• Synonyms: Voltage-gated calcium channel subunit alpha-2/delta-2
• Gene Name: CACNA2D2
• Related Disease:
  Cerebellar atrophy with seizures and variable developmental delay
  Complex neurodevelopmental disorder
• UniProt ID: CA2D2_HUMAN
• Pfam ID: PF08473 ; PF00092 ; PF08399
• Sequence:
  MAVPARTCGASRPGPARTARPWPGCGPHPGPGTRRPTSGPPRPLWLLLPLLPLLAAPGAS
  AYSFPQQHTMQHWARRLEQEVDGVMRIFGGVQQLREIYKDNRNLFEVQENEPQKLVEKVA
  GDIESLLDRKVQALKRLADAAENFQKAHRWQDNIKEEDIVYYDAKADAELDDPESEDVER
  GSKASTLRLDFIEDPNFKNKVNYSYAAVQIPTDIYKGSTVILNELNWTEALENVFMENRR
  QDPTLLWQVFGSATGVTRYYPATPWRAPKKIDLYDVRRRPWYIQGASSPKDMVIIVDVSG
  SVSGLTLKLMKTSVCEMLDTLSDDDYVNVASFNEKAQPVSCFTHLVQANVRNKKVFKEAV
  QGMVAKGTTGYKAGFEYAFDQLQNSNITRANCNKMIMMFTDGGEDRVQDVFEKYNWPNRT
  VRVFTFSVGQHNYDVTPLQWMACANKGYYFEIPSIGAIRINTQEYLDVLGRPMVLAGKEA
  KQVQWTNVYEDALGLGLVVTGTLPVFNLTQDGPGEKKNQLILGVMGIDVALNDIKRLTPN
  YTLGANGYVFAIDLNGYVLLHPNLKPQTTNFREPVTLDFLDAELEDENKEEIRRSMIDGN
  KGHKQIRTLVKSLDERYIDEVTRNYTWVPIRSTNYSLGLVLPPYSTFYLQANLSDQILQV
  KLPISKLKDFEFLLPSSFESEGHVFIAPREYCKDLNASDNNTEFLKNFIELMEKVTPDSK
  QCNNFLLHNLILDTGITQQLVERVWRDQDLNTYSLLAVFAATDGGITRVFPNKAAEDWTE
  NPEPFNASFYRRSLDNHGYVFKPPHQDALLRPLELENDTVGILVSTAVELSLGRRTLRPA
  VVGVKLDLEAWAEKFKVLASNRTHQDQPQKCGPNSHCEMDCEVNNEDLLCVLIDDGGFLV
  LSNQNHQWDQVGRFFSEVDANLMLALYNNSFYTRKESYDYQAACAPQPPGNLGAAPRGVF
  VPTVADFLNLAWWTSAAAWSLFQQLLYGLIYHSWFQADPAEAEGSPETRESSCVMKQTQY
  YFGSVNASYNAIIDCGNCSRLFHAQRLTNTNLLFVVAEKPLCSQCEAGRLLQKETHSDGP
  EQCELVQRPRYRRGPHICFDYNATEDTSDCGRGASFPPSLGVLVSLQLLLLLGLPPRPQP
  QVLVHASRRL
• Function: The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G). Overexpression induces apoptosis.
• Tissue Specificity: Predominantly present in cerebellar cortex. Present in various lung tumor cell lines, while it is absent in normal lung (at protein level). Highly expressed in heart, lung, testis, pancreas and skeletal muscle. Also expressed in kidney, liver, placenta and brain.
• 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:
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  Regulation of insulin secretion (R-HSA-422356)
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Phase 2 - plateau phase (R-HSA-5576893)
  Sensory processing of sound by inner hair cells of the cochlea (R-HSA-9662360)
  Presynaptic depolarization and calcium channel opening (R-HSA-112308)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar atrophy with seizures and variable developmental delay	DISHXT4J	Strong	Autosomal recessive	[1]
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal recessive	[2]

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-2 (CACNA2D2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[7]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[8]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[5]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[5]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Gabapentin	DM6T924	Approved	Gabapentin affects the binding of Voltage-dependent calcium channel subunit alpha-2/delta-2 (CACNA2D2).	[9]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] 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.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Arch Toxicol. 2016 Nov;90(11):2763-2777.
• [6] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [9] Tissue-specific expression and gabapentin-binding properties of calcium channel alpha2delta subunit subtypes. J Membr Biol. 2001 Nov 1;184(1):35-43. doi: 10.1007/s00232-001-0072-7.
• [10] 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.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.