Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT53K8W2)

• DOT Name: Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2)
• Synonyms: CAB2; Calcium channel voltage-dependent subunit beta 2; Lambert-Eaton myasthenic syndrome antigen B; MYSB
• Gene Name: CACNB2
• Related Disease:
  Brugada syndrome 1
  Brugada syndrome 4
  Hypertrophic cardiomyopathy
  Short QT syndrome
• UniProt ID: CACB2_HUMAN
• Pfam ID: PF00625 ; PF12052
• Sequence:
  MVQRDMSKSPPTAAAAVAQEIQMELLENVAPAGALGAAAQSYGKGARRKNRFKGSDGSTS
  SDTTSNSFVRQGSADSYTSRPSDSDVSLEEDREAVRREAERQAQAQLEKAKTKPVAFAVR
  TNVSYSAAHEDDVPVPGMAISFEAKDFLHVKEKFNNDWWIGRLVKEGCEIGFIPSPVKLE
  NMRLQHEQRAKQGKFYSSKSGGNSSSSLGDIVPSSRKSTPPSSAIDIDATGLDAEENDIP
  ANHRSPKPSANSVTSPHSKEKRMPFFKKTEHTPPYDVVPSMRPVVLVGPSLKGYEVTDMM
  QKALFDFLKHRFEGRISITRVTADISLAKRSVLNNPSKHAIIERSNTRSSLAEVQSEIER
  IFELARTLQLVVLDADTINHPAQLSKTSLAPIIVYVKISSPKVLQRLIKSRGKSQAKHLN
  VQMVAADKLAQCPPELFDVILDENQLEDACEHLADYLEAYWKATHPPSSSLPNPLLSRTL
  ATSSLPLSPTLASNSQGSQGDQRTDRSAPIRSASQAEEEPSVEPVKKSQHRSSSSAPHHN
  HRSGTSRGLSRQETFDSETQESRDSAYVEPKEDYSHDHVDHYASHRDHNHRDETHGSSDH
  RHRESRHRSRDVDREQDHNECNKQRSRHKSKDRYCEKDGEVISKKRNEAGEWNRDVYIRQ
• Function: Beta subunit of voltage-dependent calcium channels which contributes to the function of the calcium channel by increasing peak calcium current. Plays a role in shifting voltage dependencies of activation and inactivation of the channel. May modulate G protein inhibition. May contribute to beta-adrenergic augmentation of Ca(2+) influx in cardiomyocytes, thereby regulating increases in heart rate and contractile force. Involved in membrane targeting of the alpha-1 subunit CACNA1C.
• Tissue Specificity: Expressed in all tissues.
• 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)
  NCAM1 interactions (R-HSA-419037)
  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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[1]
Brugada syndrome 4	DIS29GET	Disputed	Autosomal dominant	[2]
Hypertrophic cardiomyopathy	DISQG2AI	Disputed	Autosomal dominant	[1]
Short QT syndrome	DISOI9X1	Disputed	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[9]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[10]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Voltage-dependent L-type calcium channel subunit beta-2 (CACNB2).	[12]

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] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] 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.
• [11] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [12] 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.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.