Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYAI1UO)

• DOT Name: Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4)
• Synonyms: CAB4; Calcium channel voltage-dependent subunit beta 4
• Gene Name: CACNB4
• Related Disease:
  Episodic ataxia type 5
  Juvenile myoclonic epilepsy
  Epilepsy, idiopathic generalized, susceptibility to, 13
  Epilepsy, idiopathic generalized, susceptibility to, 9
  Epilepsy
• UniProt ID: CACB4_HUMAN
• PDB ID: 2D46
• Pfam ID: PF00625 ; PF12052
• Sequence:
  MSSSSYAKNGTADGPHSPTSQVARGTTTRRSRLKRSDGSTTSTSFILRQGSADSYTSRPS
  DSDVSLEEDREAIRQEREQQAAIQLERAKSKPVAFAVKTNVSYCGALDEDVPVPSTAISF
  DAKDFLHIKEKYNNDWWIGRLVKEGCEIGFIPSPLRLENIRIQQEQKRGRFHGGKSSGNS
  SSSLGEMVSGTFRATPTSTAKQKQKVTEHIPPYDVVPSMRPVVLVGPSLKGYEVTDMMQK
  ALFDFLKHRFDGRISITRVTADISLAKRSVLNNPSKRAIIERSNTRSSLAEVQSEIERIF
  ELARSLQLVVLDADTINHPAQLIKTSLAPIIVHVKVSSPKVLQRLIKSRGKSQSKHLNVQ
  LVAADKLAQCPPEMFDVILDENQLEDACEHLGEYLEAYWRATHTTSSTPMTPLLGRNLGS
  TALSPYPTAISGLQSQRMRHSNHSTENSPIERRSLMTSDENYHNERARKSRNRLSSSSQH
  SRDHYPLVEEDYPDSYQDTYKPHRNRGSPGGYSHDSRHRL
• Function: The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting.
• Tissue Specificity: Expressed predominantly in the cerebellum and kidney.
• 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:
  NCAM1 interactions (R-HSA-419037)
  Presynaptic depolarization and calcium channel opening (R-HSA-112308)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Episodic ataxia type 5	DISC3F0L	Supportive	Autosomal dominant	[1]
Juvenile myoclonic epilepsy	DISYXV1N	Supportive	Autosomal dominant	[2]
Epilepsy, idiopathic generalized, susceptibility to, 13	DISZA3EN	Limited	Autosomal dominant	[1]
Epilepsy, idiopathic generalized, susceptibility to, 9	DISJ6PF8	Limited	Autosomal dominant	[3]
Epilepsy	DISBB28L	Refuted	Autosomal dominant	[4]

12 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 Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[11]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[12]
Thalidomide	DM70BU5	Approved	Thalidomide decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Voltage-dependent L-type calcium channel subunit beta-4 (CACNB4).	[18]

References

• [1] Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000 May;66(5):1531-9. doi: 10.1086/302909. Epub 2000 Apr 4.
• [2] The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav. 2013 Jul;28 Suppl 1:S52-7. doi: 10.1016/j.yebeh.2012.06.033.
• [3] beta subunit reshuffling modifies N- and P/Q-type Ca2+ channel subunit compositions in lethargic mouse brain. Mol Cell Neurosci. 1999 Apr;13(4):293-311. doi: 10.1006/mcne.1999.0748.
• [4] 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.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres. Int J Mol Sci. 2020 Aug 3;21(15):5564. doi: 10.3390/ijms21155564.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.