Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT96MCM2)

• DOT Name: Voltage-dependent L-type calcium channel subunit alpha-1S (CACNA1S)
• Synonyms: Calcium channel, L type, alpha-1 polypeptide, isoform 3, skeletal muscle; Voltage-gated calcium channel subunit alpha Cav1.1
• Gene Name: CACNA1S
• Related Disease:
  Congenital myopathy
  Congenital myopathy 18
  Hypokalemic periodic paralysis, type 1
  Malignant hyperthermia, susceptibility to, 5
  Hypokalemic periodic paralysis
• UniProt ID: CAC1S_HUMAN
• PDB ID: 2VAY; 6B27
• Pfam ID: PF08763 ; PF16905 ; PF00520
• Sequence:
  MEPSSPQDEGLRKKQPKKPVPEILPRPPRALFCLTLENPLRKACISIVEWKPFETIILLT
  IFANCVALAVYLPMPEDDNNSLNLGLEKLEYFFLIVFSIEAAMKIIAYGFLFHQDAYLRS
  GWNVLDFTIVFLGVFTVILEQVNVIQSHTAPMSSKGAGLDVKALRAFRVLRPLRLVSGVP
  SLQVVLNSIFKAMLPLFHIALLVLFMVIIYAIIGLELFKGKMHKTCYFIGTDIVATVENE
  EPSPCARTGSGRRCTINGSECRGGWPGPNHGITHFDNFGFSMLTVYQCITMEGWTDVLYW
  VNDAIGNEWPWIYFVTLILLGSFFILNLVLGVLSGEFTKEREKAKSRGTFQKLREKQQLD
  EDLRGYMSWITQGEVMDVEDFREGKLSLDEGGSDTESLYEIAGLNKIIQFIRHWRQWNRI
  FRWKCHDIVKSKVFYWLVILIVALNTLSIASEHHNQPLWLTRLQDIANRVLLSLFTTEML
  MKMYGLGLRQYFMSIFNRFDCFVVCSGILEILLVESGAMTPLGISVLRCIRLLRIFKITK
  YWTSLSNLVASLLNSIRSIASLLLLLFLFIVIFALLGMQLFGGRYDFEDTEVRRSNFDNF
  PQALISVFQVLTGEDWTSMMYNGIMAYGGPSYPGMLVCIYFIILFVCGNYILLNVFLAIA
  VDNLAEAESLTSAQKAKAEEKKRRKMSKGLPDKSEEEKSTMAKKLEQKPKGEGIPTTAKL
  KIDEFESNVNEVKDPYPSADFPGDDEEDEPEIPLSPRPRPLAELQLKEKAVPIPEASSFF
  IFSPTNKIRVLCHRIVNATWFTNFILLFILLSSAALAAEDPIRADSMRNQILKHFDIGFT
  SVFTVEIVLKMTTYGAFLHKGSFCRNYFNMLDLLVVAVSLISMGLESSAISVVKILRVLR
  VLRPLRAINRAKGLKHVVQCMFVAISTIGNIVLVTTLLQFMFACIGVQLFKGKFFRCTDL
  SKMTEEECRGYYYVYKDGDPMQIELRHREWVHSDFHFDNVLSAMMSLFTVSTFEGWPQLL
  YKAIDSNAEDVGPIYNNRVEMAIFFIIYIILIAFFMMNIFVGFVIVTFQEQGETEYKNCE
  LDKNQRQCVQYALKARPLRCYIPKNPYQYQVWYIVTSSYFEYLMFALIMLNTICLGMQHY
  NQSEQMNHISDILNVAFTIIFTLEMILKLMAFKARGYFGDPWNVFDFLIVIGSIIDVILS
  EIDTFLASSGGLYCLGGGCGNVDPDESARISSAFFRLFRVMRLIKLLSRAEGVRTLLWTF
  IKSFQALPYVALLIVMLFFIYAVIGMQMFGKIALVDGTQINRNNNFQTFPQAVLLLFRCA
  TGEAWQEILLACSYGKLCDPESDYAPGEEYTCGTNFAYYYFISFYMLCAFLVINLFVAVI
  MDNFDYLTRDWSILGPHHLDEFKAIWAEYDPEAKGRIKHLDVVTLLRRIQPPLGFGKFCP
  HRVACKRLVGMNMPLNSDGTVTFNATLFALVRTALKIKTEGNFEQANEELRAIIKKIWKR
  TSMKLLDQVIPPIGDDEVTVGKFYATFLIQEHFRKFMKRQEEYYGYRPKKDIVQIQAGLR
  TIEEEAAPEICRTVSGDLAAEEELERAMVEAAMEEGIFRRTGGLFGQVDNFLERTNSLPP
  VMANQRPLQFAEIEMEEMESPVFLEDFPQDPRTNPLARANTNNANANVAYGNSNHSNSHV
  FSSVHYEREFPEETETPATRGRALGQPCRVLGPHSKPCVEMLKGLLTQRAMPRGQAPPAP
  CQCPRVESSMPEDRKSSTPGSLHEETPHSRSTRENTSRCSAPATALLIQKALVRGGLGTL
  AADANFIMATGQALADACQMEPEEVEIMATELLKGREAPEGMASSLGCLNLGSSLGSLDQ
  HQGSQETLIPPRL
• Function: Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca(2+) release from the sarcoplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group.
• Tissue Specificity: Skeletal muscle specific.
• 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)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  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)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alzheimer disease (hsa05010)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway: NCAM1 interactions (R-HSA-419037)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital myopathy	DISLSK9G	Strong	Autosomal dominant	[1]
Congenital myopathy 18	DIS5GN3Y	Strong	Autosomal recessive	[2]
Hypokalemic periodic paralysis, type 1	DIS5GF2M	Strong	Autosomal dominant	[1]
Malignant hyperthermia, susceptibility to, 5	DISVMC6G	Strong	Autosomal dominant	[3]
Hypokalemic periodic paralysis	DISVIXI1	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Daunorubicin	DMQUSBT	Approved	Voltage-dependent L-type calcium channel subunit alpha-1S (CACNA1S) affects the response to substance of Daunorubicin.	[8]

2 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 L-type calcium channel subunit alpha-1S (CACNA1S).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Voltage-dependent L-type calcium channel subunit alpha-1S (CACNA1S).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Voltage-dependent L-type calcium channel subunit alpha-1S (CACNA1S).	[7]

References

• [1] 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.
• [2] Novel pathogenic variants and genes for myopathies identified by whole exome sequencing. Mol Genet Genomic Med. 2015 Jul;3(4):283-301. doi: 10.1002/mgg3.142. Epub 2015 Apr 8.
• [3] Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet. 2001 Mar;59(3):178-84. doi: 10.1034/j.1399-0004.2001.590306.x.
• [4] Hypokalemic Periodic Paralysis. 2002 Apr 30 [updated 2018 Jul 26]. 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] 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] 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.
• [8] Mapping genes that contribute to daunorubicin-induced cytotoxicity. Cancer Res. 2007 Jun 1;67(11):5425-33. doi: 10.1158/0008-5472.CAN-06-4431.