Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6KFNMS)

• DOT Name: Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C)
• Synonyms: Calcium channel, L type, alpha-1 polypeptide, isoform 1, cardiac muscle; Voltage-gated calcium channel subunit alpha Cav1.2
• Gene Name: CACNA1C
• Related Disease:
  Timothy syndrome
  Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
  Long QT syndrome
  Long qt syndrome 8
  Brugada syndrome
  Brugada syndrome 3
  Short QT syndrome
  Intellectual disability
• UniProt ID: CAC1C_HUMAN
• PDB ID: 1T0J; 2BE6; 2F3Y; 2F3Z; 2LQC; 3G43; 3OXQ; 5V2P; 5V2Q; 6C0A; 6DAD; 6DAE; 6DAF; 6U39; 6U3A; 6U3B; 6U3D; 7L8V; 8EOG; 8EOI; 8FD7; 8WE6; 8WE7; 8WE8; 8WE9; 8WEA
• Pfam ID: PF08763 ; PF16885 ; PF16905 ; PF00520
• Sequence:
  MVNENTRMYIPEENHQGSNYGSPRPAHANMNANAAAGLAPEHIPTPGAALSWQAAIDAAR
  QAKLMGSAGNATISTVSSTQRKRQQYGKPKKQGSTTATRPPRALLCLTLKNPIRRACISI
  VEWKPFEIIILLTIFANCVALAIYIPFPEDDSNATNSNLERVEYLFLIIFTVEAFLKVIA
  YGLLFHPNAYLRNGWNLLDFIIVVVGLFSAILEQATKADGANALGGKGAGFDVKALRAFR
  VLRPLRLVSGVPSLQVVLNSIIKAMVPLLHIALLVLFVIIIYAIIGLELFMGKMHKTCYN
  QEGIADVPAEDDPSPCALETGHGRQCQNGTVCKPGWDGPKHGITNFDNFAFAMLTVFQCI
  TMEGWTDVLYWVNDAVGRDWPWIYFVTLIIIGSFFVLNLVLGVLSGEFSKEREKAKARGD
  FQKLREKQQLEEDLKGYLDWITQAEDIDPENEDEGMDEEKPRNMSMPTSETESVNTENVA
  GGDIEGENCGARLAHRISKSKFSRYWRRWNRFCRRKCRAAVKSNVFYWLVIFLVFLNTLT
  IASEHYNQPNWLTEVQDTANKALLALFTAEMLLKMYSLGLQAYFVSLFNRFDCFVVCGGI
  LETILVETKIMSPLGISVLRCVRLLRIFKITRYWNSLSNLVASLLNSVRSIASLLLLLFL
  FIIIFSLLGMQLFGGKFNFDEMQTRRSTFDNFPQSLLTVFQILTGEDWNSVMYDGIMAYG
  GPSFPGMLVCIYFIILFICGNYILLNVFLAIAVDNLADAESLTSAQKEEEEEKERKKLAR
  TASPEKKQELVEKPAVGESKEEKIELKSITADGESPPATKINMDDLQPNENEDKSPYPNP
  ETTGEEDEEEPEMPVGPRPRPLSELHLKEKAVPMPEASAFFIFSSNNRFRLQCHRIVNDT
  IFTNLILFFILLSSISLAAEDPVQHTSFRNHILFYFDIVFTTIFTIEIALKILGNADYVF
  TSIFTLEIILKMTAYGAFLHKGSFCRNYFNILDLLVVSVSLISFGIQSSAINVVKILRVL
  RVLRPLRAINRAKGLKHVVQCVFVAIRTIGNIVIVTTLLQFMFACIGVQLFKGKLYTCSD
  SSKQTEAECKGNYITYKDGEVDHPIIQPRSWENSKFDFDNVLAAMMALFTVSTFEGWPEL
  LYRSIDSHTEDKGPIYNYRVEISIFFIIYIIIIAFFMMNIFVGFVIVTFQEQGEQEYKNC
  ELDKNQRQCVEYALKARPLRRYIPKNQHQYKVWYVVNSTYFEYLMFVLILLNTICLAMQH
  YGQSCLFKIAMNILNMLFTGLFTVEMILKLIAFKPKGYFSDPWNVFDFLIVIGSIIDVIL
  SETNHYFCDAWNTFDALIVVGSIVDIAITEVNPAEHTQCSPSMNAEENSRISITFFRLFR
  VMRLVKLLSRGEGIRTLLWTFIKSFQALPYVALLIVMLFFIYAVIGMQVFGKIALNDTTE
  INRNNNFQTFPQAVLLLFRCATGEAWQDIMLACMPGKKCAPESEPSNSTEGETPCGSSFA
  VFYFISFYMLCAFLIINLFVAVIMDNFDYLTRDWSILGPHHLDEFKRIWAEYDPEAKGRI
  KHLDVVTLLRRIQPPLGFGKLCPHRVACKRLVSMNMPLNSDGTVMFNATLFALVRTALRI
  KTEGNLEQANEELRAIIKKIWKRTSMKLLDQVVPPAGDDEVTVGKFYATFLIQEYFRKFK
  KRKEQGLVGKPSQRNALSLQAGLRTLHDIGPEIRRAISGDLTAEEELDKAMKEAVSAASE
  DDIFRRAGGLFGNHVSYYQSDGRSAFPQTFTTQRPLHINKAGSSQGDTESPSHEKLVDST
  FTPSSYSSTGSNANINNANNTALGRLPRPAGYPSTVSTVEGHGPPLSPAIRVQEVAWKLS
  SNRERHVPMCEDLELRRDSGSAGTQAHCLLLRKANPSRCHSRESQAAMAGQEETSQDETY
  EVKMNHDTEACSEPSLLSTEMLSYQDDENRQLTLPEEDKRDIRQSPKRGFLRSASLGRRA
  SFHLECLKRQKDRGGDISQKTVLPLHLVHHQALAVAGLSPLLQRSHSPASFPRPFATPPA
  TPGSRGWPPQPVPTLRLEGVESSEKLNSSFPSIHCGSWAETTPGGGGSSAARRVRPVSLM
  VPSQAGAPGRQFHGSASSLVEAVLISEGLGQFAQDPKFIEVTTQELADACDMTIEEMESA
  ADNILSGGAPQSPNGALLPFVNCRDAGQDRAGGEEDAGCVRARGRPSEEELQDSRVYVSS
  L
• Function: Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents. Mediates influx of calcium ions into the cytoplasm, and thereby triggers calcium release from the sarcoplasm. Plays an important role in excitation-contraction coupling in the heart. Required for normal heart development and normal regulation of heart rhythm. Required for normal contraction of smooth muscle cells in blood vessels and in the intestine. Essential for normal blood pressure regulation via its role in the contraction of arterial smooth muscle cells. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Probable); (Microbial infection) Acts as a receptor for Influenzavirus. May play a critical role in allowing virus entry when sialylated and expressed on lung tissues.
• Tissue Specificity: Detected throughout the brain, including hippocampus, cerebellum and amygdala, throughout the heart and vascular system, including ductus arteriosus, in urinary bladder, and in retina and sclera in the eye . Expressed in brain, heart, jejunum, ovary, pancreatic beta-cells and vascular smooth muscle. Overall expression is reduced in atherosclerotic vascular smooth muscle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Cardiac muscle contraction (hsa04260)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Taste transduction (hsa04742)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Oxytocin sig.ling pathway (hsa04921)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  GnRH secretion (hsa04929)
  Type II diabetes mellitus (hsa04930)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alzheimer disease (hsa05010)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  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)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Timothy syndrome	DISBXBZP	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures	DISLP2XI	Strong	Autosomal dominant	[2]
Long QT syndrome	DISMKWS3	Moderate	Autosomal dominant	[3]
Long qt syndrome 8	DIS5FEOW	Moderate	Autosomal dominant	[2]
Brugada syndrome	DISSGN0E	Supportive	Autosomal dominant	[4]
Brugada syndrome 3	DISSSLRF	Disputed	Autosomal dominant	[2]
Short QT syndrome	DISOI9X1	Disputed	Autosomal dominant	[3]
Intellectual disability	DISMBNXP	Limited	Autosomal dominant	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Atenolol	DMNKG1Z	Approved	Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C) increases the response to substance of Atenolol.	[19]
Verapamil	DMA7PEW	Phase 2/3 Trial	Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C) increases the response to substance of Verapamil.	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[9]

11 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 L-type calcium channel subunit alpha-1C (CACNA1C).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[8]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[10]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[11]
Nefazodone	DM4ZS8M	Approved	Nefazodone affects the activity of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[12]
Crizotinib	DM4F29C	Approved	Crizotinib decreases the activity of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[13]
Retigabine	DMGNYIH	Approved	Retigabine affects the activity of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[14]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[17]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Voltage-dependent L-type calcium channel subunit alpha-1C (CACNA1C).	[18]

References

• [1] Expanding the phenotype of CACNA1C mutation disorders. Mol Genet Genomic Med. 2021 Jun;9(6):e1673. doi: 10.1002/mgg3.1673. Epub 2021 Apr 1.
• [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] 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.
• [4] Brugada Syndrome. 2005 Mar 31 [updated 2022 Aug 25]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [9] 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.
• [10] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2016 Apr 1;296:42-53. doi: 10.1016/j.taap.2016.01.015. Epub 2016 Jan 25.
• [13] Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):245-55.
• [14] Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. Toxicol Appl Pharmacol. 2017 Aug 15;329:309-317. doi: 10.1016/j.taap.2017.06.018. Epub 2017 Jun 20.
• [15] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [16] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [17] 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.
• [18] Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens. 2010 Aug;28(8):1676-86. doi: 10.1097/HJH.0b013e32833b1f8e.
• [19] CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response. Circ Cardiovasc Genet. 2009 Aug;2(4):362-70. doi: 10.1161/CIRCGENETICS.109.857839. Epub 2009 Jun 3.