Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2VE9UU)

• DOT Name: Calcium release-activated calcium channel protein 1 (ORAI1)
• Synonyms: Protein orai-1; Transmembrane protein 142A
• Gene Name: ORAI1
• Related Disease:
  Tubular aggregate myopathy
  Combined immunodeficiency due to ORAI1 deficiency
  Myopathy, tubular aggregate, 2
  Stormorken syndrome
• UniProt ID: CRCM1_HUMAN
• PDB ID: 2MAK; 4EHQ
• Pfam ID: PF07856
• Sequence:
  MHPEPAPPPSRSSPELPPSGGSTTSGSRRSRRRSGDGEPPGAPPPPPSAVTYPDWIGQSY
  SEVMSLNEHSMQALSWRKLYLSRAKLKASSRTSALLSGFAMVAMVEVQLDADHDYPPGLL
  IAFSACTTVLVAVHLFALMISTCILPNIEAVSNVHNLNSVKESPHERMHRHIELAWAFST
  VIGTLLFLAEVVLLCWVKFLPLKKQPGQPRPTSKPPASGAAANVSTSGITPGQAAAIAST
  TIMVPFGLIFIVFAVHFYRSLVSHKTDRQFQELNELAEFARLQDQLDHRGDHPLTPGSHY
  A
• Function: Ca(2+) release-activated Ca(2+) (CRAC) channel subunit which mediates Ca(2+) influx following depletion of intracellular Ca(2+) stores and channel activation by the Ca(2+) sensor, STIM1. CRAC channels are the main pathway for Ca(2+) influx in T-cells and promote the immune response to pathogens by activating the transcription factor NFAT. Plays a prominent role in Ca(2+) influx at the basolateral membrane of mammary epithelial cells independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May mediate transepithelial transport of large quantities of Ca(2+) for milk secretion.
• Tissue Specificity: Expressed in naive CD4 and CD8 T cells (at protein level) . Expressed at similar levels in naive and effector T helper cells .
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Platelet activation (hsa04611)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Cortisol synthesis and secretion (hsa04927)
  Cushing syndrome (hsa04934)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  Ion homeostasis (R-HSA-5578775)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  Elevation of cytosolic Ca2+ levels (R-HSA-139853)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tubular aggregate myopathy	DISC11WH	Definitive	Autosomal dominant	[1]
Combined immunodeficiency due to ORAI1 deficiency	DISYIUEF	Strong	Autosomal recessive	[2]
Myopathy, tubular aggregate, 2	DIS6RJ7U	Strong	Autosomal dominant	[3]
Stormorken syndrome	DIS9US3H	Supportive	Autosomal dominant	[4]

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 Calcium release-activated calcium channel protein 1 (ORAI1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Calcium release-activated calcium channel protein 1 (ORAI1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[12]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[13]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the expression of Calcium release-activated calcium channel protein 1 (ORAI1).	[15]

References

• [1] 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.
• [2] A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature. 2006 May 11;441(7090):179-85. doi: 10.1038/nature04702. Epub 2006 Apr 2.
• [3] Familial myopathy with tubular aggregates associated with abnormal pupils. Neurology. 2004 Sep 28;63(6):1111-3. doi: 10.1212/01.wnl.0000138575.14424.5f.
• [4] Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4197-202. doi: 10.1073/pnas.1312520111. Epub 2014 Mar 3.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 17-Estradiol via Orai1 activates calcium mobilization to induce cell proliferation in epithelial ovarian cancer. J Biochem Mol Toxicol. 2020 Dec;34(12):e22603. doi: 10.1002/jbt.22603. Epub 2020 Aug 25.
• [10] 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.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Inhibition of store-operated Ca(2+) channels prevent ethanol-induced intracellular Ca(2+) increase and cell injury in a human hepatoma cell line. Toxicol Lett. 2012 Feb 5;208(3):254-61. doi: 10.1016/j.toxlet.2011.11.007. Epub 2011 Nov 17.
• [14] 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.
• [15] Endoplasmic Reticulum Stress and Store-Operated Calcium Entry Contribute to Usnic Acid-Induced Toxicity in Hepatic Cells. Toxicol Sci. 2015 Jul;146(1):116-26. doi: 10.1093/toxsci/kfv075. Epub 2015 Apr 13.