Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY08SIX)

• DOT Name: Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A)
• Synonyms: Brain calcium channel I; BI; Calcium channel, L type, alpha-1 polypeptide isoform 4; Voltage-gated calcium channel subunit alpha Cav2.1
• Gene Name: CACNA1A
• Related Disease:
  Episodic ataxia type 2
  Undetermined early-onset epileptic encephalopathy
  Developmental and epileptic encephalopathy, 42
  Migraine, familial hemiplegic, 1
  Spinocerebellar ataxia type 6
  Benign paroxysmal torticollis of infancy
  Familial or sporadic hemiplegic migraine
  LennoxGastaut syndrome
• UniProt ID: CAC1A_HUMAN
• PDB ID: 3BXK
• Pfam ID: PF08763 ; PF16905 ; PF00520
• Sequence:
  MARFGDEMPARYGGGGSGAAAGVVVGSGGGRGAGGSRQGGQPGAQRMYKQSMAQRARTMA
  LYNPIPVRQNCLTVNRSLFLFSEDNVVRKYAKKITEWPPFEYMILATIIANCIVLALEQH
  LPDDDKTPMSERLDDTEPYFIGIFCFEAGIKIIALGFAFHKGSYLRNGWNVMDFVVVLTG
  ILATVGTEFDLRTLRAVRVLRPLKLVSGIPSLQVVLKSIMKAMIPLLQIGLLLFFAILIF
  AIIGLEFYMGKFHTTCFEEGTDDIQGESPAPCGTEEPARTCPNGTKCQPYWEGPNNGITQ
  FDNILFAVLTVFQCITMEGWTDLLYNSNDASGNTWNWLYFIPLIIIGSFFMLNLVLGVLS
  GEFAKERERVENRRAFLKLRRQQQIERELNGYMEWISKAEEVILAEDETDGEQRHPFDAL
  RRTTIKKSKTDLLNPEEAEDQLADIASVGSPFARASIKSAKLENSTFFHKKERRMRFYIR
  RMVKTQAFYWTVLSLVALNTLCVAIVHYNQPEWLSDFLYYAEFIFLGLFMSEMFIKMYGL
  GTRPYFHSSFNCFDCGVIIGSIFEVIWAVIKPGTSFGISVLRALRLLRIFKVTKYWASLR
  NLVVSLLNSMKSIISLLFLLFLFIVVFALLGMQLFGGQFNFDEGTPPTNFDTFPAAIMTV
  FQILTGEDWNEVMYDGIKSQGGVQGGMVFSIYFIVLTLFGNYTLLNVFLAIAVDNLANAQ
  ELTKDEQEEEEAANQKLALQKAKEVAEVSPLSAANMSIAVKEQQKNQKPAKSVWEQRTSE
  MRKQNLLASREALYNEMDPDERWKAAYTRHLRPDMKTHLDRPLVVDPQENRNNNTNKSRA
  AEPTVDQRLGQQRAEDFLRKQARYHDRARDPSGSAGLDARRPWAGSQEAELSREGPYGRE
  SDHHAREGSLEQPGFWEGEAERGKAGDPHRRHVHRQGGSRESRSGSPRTGADGEHRRHRA
  HRRPGEEGPEDKAERRARHREGSRPARGGEGEGEGPDGGERRRRHRHGAPATYEGDARRE
  DKERRHRRRKENQGSGVPVSGPNLSTTRPIQQDLGRQDPPLAEDIDNMKNNKLATAESAA
  PHGSLGHAGLPQSPAKMGNSTDPGPMLAIPAMATNPQNAASRRTPNNPGNPSNPGPPKTP
  ENSLIVTNPSGTQTNSAKTARKPDHTTVDIPPACPPPLNHTVVQVNKNANPDPLPKKEEE
  KKEEEEDDRGEDGPKPMPPYSSMFILSTTNPLRRLCHYILNLRYFEMCILMVIAMSSIAL
  AAEDPVQPNAPRNNVLRYFDYVFTGVFTFEMVIKMIDLGLVLHQGAYFRDLWNILDFIVV
  SGALVAFAFTGNSKGKDINTIKSLRVLRVLRPLKTIKRLPKLKAVFDCVVNSLKNVFNIL
  IVYMLFMFIFAVVAVQLFKGKFFHCTDESKEFEKDCRGKYLLYEKNEVKARDREWKKYEF
  HYDNVLWALLTLFTVSTGEGWPQVLKHSVDATFENQGPSPGYRMEMSIFYVVYFVVFPFF
  FVNIFVALIIITFQEQGDKMMEEYSLEKNERACIDFAISAKPLTRHMPQNKQSFQYRMWQ
  FVVSPPFEYTIMAMIALNTIVLMMKFYGASVAYENALRVFNIVFTSLFSLECVLKVMAFG
  ILNYFRDAWNIFDFVTVLGSITDILVTEFGNNFINLSFLRLFRAARLIKLLRQGYTIRIL
  LWTFVQSFKALPYVCLLIAMLFFIYAIIGMQVFGNIGIDVEDEDSDEDEFQITEHNNFRT
  FFQALMLLFRSATGEAWHNIMLSCLSGKPCDKNSGILTRECGNEFAYFYFVSFIFLCSFL
  MLNLFVAVIMDNFEYLTRDSSILGPHHLDEYVRVWAEYDPAAWGRMPYLDMYQMLRHMSP
  PLGLGKKCPARVAYKRLLRMDLPVADDNTVHFNSTLMALIRTALDIKIAKGGADKQQMDA
  ELRKEMMAIWPNLSQKTLDLLVTPHKSTDLTVGKIYAAMMIMEYYRQSKAKKLQAMREEQ
  DRTPLMFQRMEPPSPTQEGGPGQNALPSTQLDPGGALMAHESGLKESPSWVTQRAQEMFQ
  KTGTWSPEQGPPTDMPNSQPNSQSVEMREMGRDGYSDSEHYLPMEGQGRAASMPRLPAEN
  QRRRGRPRGNNLSTISDTSPMKRSASVLGPKARRLDDYSLERVPPEENQRHHQRRRDRSH
  RASERSLGRYTDVDTGLGTDLSMTTQSGDLPSKERDQERGRPKDRKHRQHHHHHHHHHHP
  PPPDKDRYAQERPDHGRARARDQRWSRSPSEGREHMAHRQGSSSVSGSPAPSTSGTSTPR
  RGRRQLPQTPSTPRPHVSYSPVIRKAGGSGPPQQQQQQQQQQQQQAVARPGRAATSGPRR
  YPGPTAEPLAGDRPPTGGHSSGRSPRMERRVPGPARSESPRACRHGGARWPASGPHVSEG
  PPGPRHHGYYRGSDYDEADGPGSGGGEEAMAGAYDAPPPVRHASSGATGRSPRTPRASGP
  ACASPSRHGRRLPNGYYPAHGLARPRGPGSRKGLHEPYSESDDDWC
• 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-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA (AC P54282). They are however insensitive to dihydropyridines (DHP).
• Tissue Specificity: Brain specific; mainly found in cerebellum, cerebral cortex, thalamus and hypothalamus. Expressed in the small cell lung carcinoma cell line SCC-9. No expression in heart, kidney, liver or muscle. Purkinje cells contain predominantly P-type VSCC, the Q-type being a prominent calcium current in cerebellar granule cells.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  Sy.ptic vesicle cycle (hsa04721)
  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)
  Long-term depression (hsa04730)
  Taste transduction (hsa04742)
  Type II diabetes mellitus (hsa04930)
  Spinocerebellar ataxia (hsa05017)
  Morphine addiction (hsa05032)
  Nicotine addiction (hsa05033)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  Regulation of insulin secretion (R-HSA-422356)
  Presynaptic depolarization and calcium channel opening (R-HSA-112308)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Episodic ataxia type 2	DISQ76GV	Definitive	Autosomal dominant	[1]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Definitive	Autosomal dominant	[2]
Developmental and epileptic encephalopathy, 42	DISO0BHK	Strong	Autosomal dominant	[3]
Migraine, familial hemiplegic, 1	DISF1GUO	Strong	Autosomal dominant	[4]
Spinocerebellar ataxia type 6	DISH7224	Strong	Autosomal dominant	[4]
Benign paroxysmal torticollis of infancy	DISOWC5W	Supportive	Autosomal dominant	[5]
Familial or sporadic hemiplegic migraine	DISOSL2O	Supportive	Autosomal dominant	[6]
LennoxGastaut syndrome	DISOTGO5	Supportive	Autosomal dominant	[7]

11 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 P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[10]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[19]

2 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 decreases the methylation of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Voltage-dependent P/Q-type calcium channel subunit alpha-1A (CACNA1A).	[20]

References

• [1] 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.
• [2] De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. Am J Hum Genet. 2016 Aug 4;99(2):287-98. doi: 10.1016/j.ajhg.2016.06.003. Epub 2016 Jul 28.
• [3] Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy. J Physiol. 2010 Jun 1;588(Pt 11):1905-13. doi: 10.1113/jphysiol.2009.186437. Epub 2010 Feb 15.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Benign paroxysmal torticollis of infancy: four new cases and linkage to CACNA1A mutation. Dev Med Child Neurol. 2002 Jul;44(7):490-3. doi: 10.1017/s0012162201002407.
• [6] Familial Hemiplegic Migraine. 2001 Jul 17 [updated 2021 Apr 29]. 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.
• [7] Both gain-of-function and loss-of-function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox-Gastaut syndrome. Epilepsia. 2019 Sep;60(9):1881-1894. doi: 10.1111/epi.16316. Epub 2019 Aug 29.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] 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.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] 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.
• [16] 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.
• [17] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [18] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [19] 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.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.