Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRH8X8A)

DOT Name Voltage-dependent T-type calcium channel subunit alpha-1I (CACNA1I)
Synonyms Voltage-gated calcium channel subunit alpha Cav3.3; Ca(v)3.3
Gene Name CACNA1I
Related Disease
Neurodevelopmental disorder with speech impairment and with or without seizures ( )
Complex neurodevelopmental disorder ( )
UniProt ID
CAC1I_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
7WLI; 7WLJ; 7WLK; 7WLL
Pfam ID
PF00520
Sequence
MAESASPPSSSAAAPAAEPGVTTEQPGPRSPPSSPPGLEEPLDGADPHVPHPDLAPIAFF
CLRQTTSPRNWCIKMVCNPWFECVSMLVILLNCVTLGMYQPCDDMDCLSDRCKILQVFDD
FIFIFFAMEMVLKMVALGIFGKKCYLGDTWNRLDFFIVMAGMVEYSLDLQNINLSAIRTV
RVLRPLKAINRVPSMRILVNLLLDTLPMLGNVLLLCFFVFFIFGIIGVQLWAGLLRNRCF
LEENFTIQGDVALPPYYQPEEDDEMPFICSLSGDNGIMGCHEIPPLKEQGRECCLSKDDV
YDFGAGRQDLNASGLCVNWNRYYNVCRTGSANPHKGAINFDNIGYAWIVIFQVITLEGWV
EIMYYVMDAHSFYNFIYFILLIIVGSFFMINLCLVVIATQFSETKQREHRLMLEQRQRYL
SSSTVASYAEPGDCYEEIFQYVCHILRKAKRRALGLYQALQSRRQALGPEAPAPAKPGPH
AKEPRHYHGKTKGQGDEGRHLGSRHCQTLHGPASPGNDHSGRELCPQHSPLDATPHTLVQ
PIPATLASDPASCPCCQHEDGRRPSGLGSTDSGQEGSGSGSSAGGEDEADGDGARSSEDG
ASSELGKEEEEEEQADGAVWLCGDVWRETRAKLRGIVDSKYFNRGIMMAILVNTVSMGIE
HHEQPEELTNILEICNVVFTSMFALEMILKLAAFGLFDYLRNPYNIFDSIIVIISIWEIV
GQADGGLSVLRTFRLLRVLKLVRFMPALRRQLVVLMKTMDNVATFCMLLMLFIFIFSILG
MHIFGCKFSLRTDTGDTVPDRKNFDSLLWAIVTVFQILTQEDWNVVLYNGMASTSPWASL
YFVALMTFGNYVLFNLLVAILVEGFQAEGDANRSYSDEDQSSSNIEEFDKLQEGLDSSGD
PKLCPIPMTPNGHLDPSLPLGGHLGPAGAAGPAPRLSLQPDPMLVALGSRKSSVMSLGRM
SYDQRSLSSSRSSYYGPWGRSAAWASRRSSWNSLKHKPPSAEHESLLSAERGGGARVCEV
AADEGPPRAAPLHTPHAHHIHHGPHLAHRHRHHRRTLSLDNRDSVDLAELVPAVGAHPRA
AWRAAGPAPGHEDCNGRMPSIAKDVFTKMGDRGDRGEDEEEIDYTLCFRVRKMIDVYKPD
WCEVREDWSVYLFSPENRFRVLCQTIIAHKLFDYVVLAFIFLNCITIALERPQIEAGSTE
RIFLTVSNYIFTAIFVGEMTLKVVSLGLYFGEQAYLRSSWNVLDGFLVFVSIIDIVVSLA
SAGGAKILGVLRVLRLLRTLRPLRVISRAPGLKLVVETLISSLKPIGNIVLICCAFFIIF
GILGVQLFKGKFYHCLGVDTRNITNRSDCMAANYRWVHHKYNFDNLGQALMSLFVLASKD
GWVNIMYNGLDAVAVDQQPVTNHNPWMLLYFISFLLIVSFFVLNMFVGVVVENFHKCRQH
QEAEEARRREEKRLRRLEKKRRKAQRLPYYATYCHTRLLIHSMCTSHYLDIFITFIICLN
VVTMSLEHYNQPTSLETALKYCNYMFTTVFVLEAVLKLVAFGLRRFFKDRWNQLDLAIVL
LSVMGITLEEIEINAALPINPTIIRIMRVLRIARVLKLLKMATGMRALLDTVVQALPQVG
NLGLLFMLLFFIYAALGVELFGKLVCNDENPCEGMSRHATFENFGMAFLTLFQVSTGDNW
NGIMKDTLRDCTHDERSCLSSLQFVSPLYFVSFVLTAQFVLINVVVAVLMKHLDDSNKEA
QEDAEMDAELELEMAHGLGPGPRLPTGSPGAPGRGPGGAGGGGDTEGGLCRRCYSPAQEN
LWLDSVSLIIKDSLEGELTIIDNLSGSIFHHYSSPAGCKKCHHDKQEVQLAETEAFSLNS
DRSSSILLGDDLSLEDPTACPPGRKDSKGELDPPEPMRVGDLGECFFPLSSTAVSPDPEN
FLCEMEEIPFNPVRSWLKHDSSQAPPSPFSPDASSPLLPMPAEFFHPAVSASQKGPEKGT
GTGTLPKIALQGSWASLRSPRVNCTLLRQATGSDTSLDASPSSSAGSLQTTLEDSLTLSD
SPRRALGPPAPAPGPRAGLSPAARRRLSLRGRGLFSLRGLRAHQRSHSSGGSTSPGCTHH
DSMDPSDEEGRGGAGGGGAGSEHSETLSSLSLTSLFCPPPPPPAPGLTPARKFSSTSSLA
APGRPHAAALAHGLARSPSWAADRSKDPPGRAPLPMGLGPLAPPPQPLPGELEPGDAASK
RKR
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. This channel gives rise to T-type calcium currents. T-type calcium channels belong to the 'low-voltage activated (LVA)' group and are strongly blocked by nickel and mibefradil. A particularity of this type of channels 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. Gates in voltage ranges similar to, but higher than alpha 1G or alpha 1H.
Tissue Specificity Brain specific.
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 )
Cushing syndrome (hsa04934 )
Reactome Pathway
Smooth Muscle Contraction (R-HSA-445355 )
NCAM1 interactions (R-HSA-419037 )

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Neurodevelopmental disorder with speech impairment and with or without seizures DISGSXGX Strong Autosomal dominant [1]
Complex neurodevelopmental disorder DISB9AFI Moderate Autosomal dominant [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of Voltage-dependent T-type calcium channel subunit alpha-1I (CACNA1I). [3]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the methylation of Voltage-dependent T-type calcium channel subunit alpha-1I (CACNA1I). [6]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Voltage-dependent T-type calcium channel subunit alpha-1I (CACNA1I). [7]
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3 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Estradiol DMUNTE3 Approved Estradiol increases the expression of Voltage-dependent T-type calcium channel subunit alpha-1I (CACNA1I). [4]
Irinotecan DMP6SC2 Approved Irinotecan decreases the expression of Voltage-dependent T-type calcium channel subunit alpha-1I (CACNA1I). [5]
Genistein DM0JETC Phase 2/3 Genistein increases the expression of Voltage-dependent T-type calcium channel subunit alpha-1I (CACNA1I). [4]
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References

1 CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders. Brain. 2021 Aug 17;144(7):2092-2106. doi: 10.1093/brain/awab101.
2 Whole exome sequencing of Rett syndrome-like patients reveals the mutational diversity of the clinical phenotype. Hum Genet. 2016 Dec;135(12):1343-1354. doi: 10.1007/s00439-016-1721-3. Epub 2016 Aug 19.
3 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.
4 Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
5 Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
6 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.
7 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.