Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGKBRE4)

• DOT Name: Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G)
• Synonyms: Cav3.1c; NBR13; Voltage-gated calcium channel subunit alpha Cav3.1
• Gene Name: CACNA1G
• Related Disease:
  Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits
  Spinocerebellar ataxia type 42
  Intellectual disability
• UniProt ID: CAC1G_HUMAN
• PDB ID: 6KZO; 6KZP
• Pfam ID: PF00520
• Sequence:
  MDEEEDGAGAEESGQPRSFMRLNDLSGAGGRPGPGSAEKDPGSADSEAEGLPYPALAPVV
  FFYLSQDSRPRSWCLRTVCNPWFERISMLVILLNCVTLGMFRPCEDIACDSQRCRILQAF
  DDFIFAFFAVEMVVKMVALGIFGKKCYLGDTWNRLDFFIVIAGMLEYSLDLQNVSFSAVR
  TVRVLRPLRAINRVPSMRILVTLLLDTLPMLGNVLLLCFFVFFIFGIVGVQLWAGLLRNR
  CFLPENFSLPLSVDLERYYQTENEDESPFICSQPRENGMRSCRSVPTLRGDGGGGPPCGL
  DYEAYNSSSNTTCVNWNQYYTNCSAGEHNPFKGAINFDNIGYAWIAIFQVITLEGWVDIM
  YFVMDAHSFYNFIYFILLIIVGSFFMINLCLVVIATQFSETKQRESQLMREQRVRFLSNA
  STLASFSEPGSCYEELLKYLVYILRKAARRLAQVSRAAGVRVGLLSSPAPLGGQETQPSS
  SCSRSHRRLSVHHLVHHHHHHHHHYHLGNGTLRAPRASPEIQDRDANGSRRLMLPPPSTP
  ALSGAPPGGAESVHSFYHADCHLEPVRCQAPPPRSPSEASGRTVGSGKVYPTVHTSPPPE
  TLKEKALVEVAASSGPPTLTSLNIPPGPYSSMHKLLETQSTGACQSSCKISSPCLKADSG
  ACGPDSCPYCARAGAGEVELADREMPDSDSEAVYEFTQDAQHSDLRDPHSRRQRSLGPDA
  EPSSVLAFWRLICDTFRKIVDSKYFGRGIMIAILVNTLSMGIEYHEQPEELTNALEISNI
  VFTSLFALEMLLKLLVYGPFGYIKNPYNIFDGVIVVISVWEIVGQQGGGLSVLRTFRLMR
  VLKLVRFLPALQRQLVVLMKTMDNVATFCMLLMLFIFIFSILGMHLFGCKFASERDGDTL
  PDRKNFDSLLWAIVTVFQILTQEDWNKVLYNGMASTSSWAALYFIALMTFGNYVLFNLLV
  AILVEGFQAEEISKREDASGQLSCIQLPVDSQGGDANKSESEPDFFSPSLDGDGDRKKCL
  ALVSLGEHPELRKSLLPPLIIHTAATPMSLPKSTSTGLGEALGPASRRTSSSGSAEPGAA
  HEMKSPPSARSSPHSPWSAASSWTSRRSSRNSLGRAPSLKRRSPSGERRSLLSGEGQESQ
  DEEESSEEERASPAGSDHRHRGSLEREAKSSFDLPDTLQVPGLHRTASGRGSASEHQDCN
  GKSASGRLARALRPDDPPLDGDDADDEGNLSKGERVRAWIRARLPACCLERDSWSAYIFP
  PQSRFRLLCHRIITHKMFDHVVLVIIFLNCITIAMERPKIDPHSAERIFLTLSNYIFTAV
  FLAEMTVKVVALGWCFGEQAYLRSSWNVLDGLLVLISVIDILVSMVSDSGTKILGMLRVL
  RLLRTLRPLRVISRAQGLKLVVETLMSSLKPIGNIVVICCAFFIIFGILGVQLFKGKFFV
  CQGEDTRNITNKSDCAEASYRWVRHKYNFDNLGQALMSLFVLASKDGWVDIMYDGLDAVG
  VDQQPIMNHNPWMLLYFISFLLIVAFFVLNMFVGVVVENFHKCRQHQEEEEARRREEKRL
  RRLEKKRRNLMLDDVIASGSSASAASEAQCKPYYSDYSRFRLLVHHLCTSHYLDLFITGV
  IGLNVVTMAMEHYQQPQILDEALKICNYIFTVIFVLESVFKLVAFGFRRFFQDRWNQLDL
  AIVLLSIMGITLEEIEVNASLPINPTIIRIMRVLRIARVLKLLKMAVGMRALLDTVMQAL
  PQVGNLGLLFMLLFFIFAALGVELFGDLECDETHPCEGLGRHATFRNFGMAFLTLFRVST
  GDNWNGIMKDTLRDCDQESTCYNTVISPIYFVSFVLTAQFVLVNVVIAVLMKHLEESNKE
  AKEEAELEAELELEMKTLSPQPHSPLGSPFLWPGVEGPDSPDSPKPGALHPAAHARSASH
  FSLEHPTDRQLFDTISLLIQGSLEWELKLMDELAGPGGQPSAFPSAPSLGGSDPQIPLAE
  MEALSLTSEIVSEPSCSLALTDDSLPDDMHTLLLSALESNMQPHPTELPGPDLLTVRKSG
  VSRTHSLPNDSYMCRHGSTAEGPLGHRGWGLPKAQSGSVLSVHSQPADTSYILQLPKDAP
  HLLQPHSAPTWGTIPKLPPPGRSPLAQRPLRRQAAIRTDSLDVQGLGSREDLLAEVSGPS
  PPLARAYSFWGQSSTQAQQHSRSHSKISKHMTPPAPCPGPEPNWGKGPPETRSSLELDTE
  LSWISGDLLPPGGQEEPPSPRDLKKCYSVEAQSCQRRPTSWLDEQRRHSIAVSCLDSGSQ
  PHLGTDPSNLGGQPLGGPGSRPKKKLSPPSITIDPPESQGPRTPPSPGICLRRRAPSSDS
  KDPLASGPPDSMAASPSPKKDVLSLSGLSSDPADLDP
• Function: Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1G gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and a voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes.
• Tissue Specificity: Highly expressed in brain, in particular in the amygdala, subthalamic nuclei, cerebellum and thalamus. Moderate expression in heart; low expression in placenta, kidney and lung. Also expressed in colon and bone marrow and in tumoral cells to a lesser extent. Highly expressed in fetal brain, but also in peripheral fetal tissues as heart, kidney and lung, suggesting a developmentally regulated expression.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  Circadian entrainment (hsa04713)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  GnRH secretion (hsa04929)
  Type II diabetes mellitus (hsa04930)
  Cushing syndrome (hsa04934)
• Reactome Pathway:
  Smooth Muscle Contraction (R-HSA-445355)
  NCAM1 interactions (R-HSA-419037)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits	DISJDFDJ	Definitive	Autosomal dominant	[1]
Spinocerebellar ataxia type 42	DIS93J3F	Definitive	Autosomal dominant	[1]
Intellectual disability	DISMBNXP	Limited	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mibefradil	DMU9VDS	Phase 1	Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G) affects the response to substance of Mibefradil.	[13]

10 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 T-type calcium channel subunit alpha-1G (CACNA1G).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[7]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[8]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone decreases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[4]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[4]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[12]

2 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 T-type calcium channel subunit alpha-1G (CACNA1G).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Voltage-dependent T-type calcium channel subunit alpha-1G (CACNA1G).	[10]

References

• [1] A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. Am J Hum Genet. 2015 Nov 5;97(5):726-37. doi: 10.1016/j.ajhg.2015.09.007. Epub 2015 Oct 8.
• [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] 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.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [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] 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.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] 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.
• [13] The Ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms. Mol Pharmacol. 2002 Aug;62(2):210-9. doi: 10.1124/mol.62.2.210.