Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEH9HGE)

• DOT Name: Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3)
• Synonyms: Voltage-gated calcium channel subunit alpha-2/delta-3
• Gene Name: CACNA2D3
• UniProt ID: CA2D3_HUMAN
• Pfam ID: PF08473 ; PF13768 ; PF08399
• Sequence:
  MAGPGSPRRASRGASALLAAALLYAALGDVVRSEQQIPLSVVKLWASAFGGEIKSIAAKY
  SGSQLLQKKYKEYEKDVAIEEIDGLQLVKKLAKNMEEMFHKKSEAVRRLVEAAEEAHLKH
  EFDADLQYEYFNAVLINERDKDGNFLELGKEFILAPNDHFNNLPVNISLSDVQVPTNMYN
  KDPAIVNGVYWSESLNKVFVDNFDRDPSLIWQYFGSAKGFFRQYPGIKWEPDENGVIAFD
  CRNRKWYIQAATSPKDVVILVDVSGSMKGLRLTIAKQTVSSILDTLGDDDFFNIIAYNEE
  LHYVEPCLNGTLVQADRTNKEHFREHLDKLFAKGIGMLDIALNEAFNILSDFNHTGQGSI
  CSQAIMLITDGAVDTYDTIFAKYNWPDRKVRIFTYLIGREAAFADNLKWMACANKGFFTQ
  ISTLADVQENVMEYLHVLSRPKVIDQEHDVVWTEAYIDSTLPQAQKLTDDQGPVLMTTVA
  MPVFSKQNETRSKGILLGVVGTDVPVKELLKTIPKYKLGIHGYAFAITNNGYILTHPELR
  LLYEEGKKRRKPNYSSVDLSEVEWEDRDDVLRNAMVNRKTGKFSMEVKKTVDKGKRVLVM
  TNDYYYTDIKGTPFSLGVALSRGHGKYFFRGNVTIEEGLHDLEHPDVSLADEWSYCNTDL
  HPEHRHLSQLEAIKLYLKGKEPLLQCDKELIQEVLFDAVVSAPIEAYWTSLALNKSENSD
  KGVEVAFLGTRTGLSRINLFVGAEQLTNQDFLKAGDKENIFNADHFPLWYRRAAEQIPGS
  FVYSIPFSTGPVNKSNVVTASTSIQLLDERKSPVVAAVGIQMKLEFFQRKFWTASRQCAS
  LDGKCSISCDDETVNCYLIDNNGFILVSEDYTQTGDFFGEIEGAVMNKLLTMGSFKRITL
  YDYQAMCRANKESSDGAHGLLDPYNAFLSAVKWIMTELVLFLVEFNLCSWWHSDMTAKAQ
  KLKQTLEPCDTEYPAFVSERTIKETTGNIACEDCSKSFVIQQIPSSNLFMVVVDSSCLCE
  SVAPITMAPIEIRYNESLKCERLKAQKIRRRPESCHGFHPEENARECGGAPSLQAQTVLL
  LLPLLLMLFSR
• 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) but not T-type (CACNA1G).
• Tissue Specificity: Only detected in brain. Not present in lung, testis, aorta, spleen, jejunum, ventricular muscle and kidney (at protein level). According to PubMed:11687876, it is brain-specific, while according to PubMed:11245980, it is widely expressed.
• 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: Presynaptic depolarization and calcium channel opening (R-HSA-112308)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[1]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[2]
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the expression of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[4]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[6]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Voltage-dependent calcium channel subunit alpha-2/delta-3 (CACNA2D3).	[3]

References

• [1] 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.
• [2] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [3] 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.
• [4] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [5] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [6] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [7] 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.