Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1NPZ9T)

• DOT Name: Plasma membrane calcium-transporting ATPase 2 (ATP2B2)
• Synonyms: PMCA2; EC 7.2.2.10; Plasma membrane calcium ATPase isoform 2; Plasma membrane calcium pump isoform 2
• Gene Name: ATP2B2
• Related Disease:
  Breast cancer
  Familial hypocalciuric hypercalcemia
  Narcolepsy
  Autism
  Autism spectrum disorder
  Autosomal recessive nonsyndromic hearing loss 12
  Breast neoplasm
  Cataract
  Cerebellar ataxia
  Deafness
  Hearing loss, autosomal dominant 82
  High blood pressure
  Invasive breast carcinoma
  Matthew-Wood syndrome
  Multiple sclerosis
  Neoplasm
  Nervous system inflammation
  Opioid dependence
  Schizophrenia
  Type-1/2 diabetes
  Von hippel-lindau disease
  Niemann-Pick disease type A
  Sensorineural hearing loss disorder
  Advanced cancer
  Bipolar disorder
  Essential hypertension
  Fetal growth restriction
  Neuralgia
  Wolfram syndrome 1
• UniProt ID: AT2B2_HUMAN
• EC Number: 7.2.2.10
• Pfam ID: PF12424 ; PF13246 ; PF00689 ; PF00690 ; PF00122 ; PF00702
• Sequence:
  MGDMTNSDFYSKNQRNESSHGGEFGCTMEELRSLMELRGTEAVVKIKETYGDTEAICRRL
  KTSPVEGLPGTAPDLEKRKQIFGQNFIPPKKPKTFLQLVWEALQDVTLIILEIAAIISLG
  LSFYHPPGEGNEGCATAQGGAEDEGEAEAGWIEGAAILLSVICVVLVTAFNDWSKEKQFR
  GLQSRIEQEQKFTVVRAGQVVQIPVAEIVVGDIAQVKYGDLLPADGLFIQGNDLKIDESS
  LTGESDQVRKSVDKDPMLLSGTHVMEGSGRMLVTAVGVNSQTGIIFTLLGAGGEEEEKKD
  KKGVKKGDGLQLPAADGAAASNAADSANASLVNGKMQDGNVDASQSKAKQQDGAAAMEMQ
  PLKSAEGGDADDRKKASMHKKEKSVLQGKLTKLAVQIGKAGLVMSAITVIILVLYFTVDT
  FVVNKKPWLPECTPVYVQYFVKFFIIGVTVLVVAVPEGLPLAVTISLAYSVKKMMKDNNL
  VRHLDACETMGNATAICSDKTGTLTTNRMTVVQAYVGDVHYKEIPDPSSINTKTMELLIN
  AIAINSAYTTKILPPEKEGALPRQVGNKTECGLLGFVLDLKQDYEPVRSQMPEEKLYKVY
  TFNSVRKSMSTVIKLPDESFRMYSKGASEIVLKKCCKILNGAGEPRVFRPRDRDEMVKKV
  IEPMACDGLRTICVAYRDFPSSPEPDWDNENDILNELTCICVVGIEDPVRPEVPEAIRKC
  QRAGITVRMVTGDNINTARAIAIKCGIIHPGEDFLCLEGKEFNRRIRNEKGEIEQERIDK
  IWPKLRVLARSSPTDKHTLVKGIIDSTHTEQRQVVAVTGDGTNDGPALKKADVGFAMGIA
  GTDVAKEASDIILTDDNFSSIVKAVMWGRNVYDSISKFLQFQLTVNVVAVIVAFTGACIT
  QDSPLKAVQMLWVNLIMDTFASLALATEPPTETLLLRKPYGRNKPLISRTMMKNILGHAV
  YQLALIFTLLFVGEKMFQIDSGRNAPLHSPPSEHYTIIFNTFVMMQLFNEINARKIHGER
  NVFDGIFRNPIFCTIVLGTFAIQIVIVQFGGKPFSCSPLQLDQWMWCIFIGLGELVWGQV
  IATIPTSRLKFLKEAGRLTQKEEIPEEELNEDVEEIDHAERELRRGQILWFRGLNRIQTQ
  IRVVKAFRSSLYEGLEKPESRTSIHNFMAHPEFRIEDSQPHIPLIDDTDLEEDAALKQNS
  SPPSSLNKNNSAIDSGINLTTDTSKSATSSSPGSPIHSLETSL
• Function: ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels in specialized cells of cerebellar circuit and vestibular and cochlear systems. Uses ATP as an energy source to transport cytosolic Ca(2+) ions across the plasma membrane to the extracellular compartment. Has fast activation and Ca(2+) clearance rate suited to control fast neuronal Ca(2+) dynamics. At parallel fiber to Purkinje neuron synapse, mediates presynaptic Ca(2+) efflux in response to climbing fiber-induced Ca(2+) rise. Provides for fast return of Ca(2+) concentrations back to their resting levels, ultimately contributing to long-term depression induction and motor learning. Plays an essential role in hearing and balance. In cochlear hair cells, shuttles Ca(2+) ions from stereocilia to the endolymph and dissipates Ca(2+) transients generated by the opening of the mechanoelectrical transduction channels. Regulates Ca(2+) levels in the vestibular system, where it contributes to the formation of otoconia. In non-excitable cells, regulates Ca(2+) signaling through spatial control of Ca(2+) ions extrusion and dissipation of Ca(2+) transients generated by store-operated channels. In lactating mammary gland, allows for the high content of Ca(2+) ions in the milk.
• Tissue Specificity: Mainly expressed in brain cortex. Found in low levels in skeletal muscle, heart muscle, stomach, liver, kidney and lung. Isoforms containing segment B are found in brain cortex and at low levels in other tissues. Isoforms containing segments X and W are found at low levels in all tissues. Isoforms containing segment A and segment Z are found at low levels in skeletal muscle and heart muscle.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Aldosterone synthesis and secretion (hsa04925)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Salivary secretion (hsa04970)
  Pancreatic secretion (hsa04972)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  (Name not found)
  Ion homeostasis (R-HSA-5578775)
  Ion transport by P-type ATPases (R-HSA-936837)
  Reduction of cytosolic Ca++ levels (R-HSA-418359)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Altered Expression	[1]
Familial hypocalciuric hypercalcemia	DIS0K7FK	Definitive	Altered Expression	[2]
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[3]
Autism	DISV4V1Z	Strong	Genetic Variation	[4]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[5]
Autosomal recessive nonsyndromic hearing loss 12	DISQU2W3	Strong	Autosomal dominant	[6]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[7]
Cataract	DISUD7SL	Strong	Altered Expression	[8]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[9]
Deafness	DISKCLH4	Strong	Genetic Variation	[6]
Hearing loss, autosomal dominant 82	DIS78B8D	Strong	Autosomal dominant	[10]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[11]
Invasive breast carcinoma	DISANYTW	Strong	Altered Expression	[12]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[13]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[7]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[15]
Opioid dependence	DIS6WEHK	Strong	Biomarker	[16]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[17]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[18]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Genetic Variation	[19]
Niemann-Pick disease type A	DISRCINF	moderate	Biomarker	[20]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Biomarker	[21]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[22]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[23]
Essential hypertension	DIS7WI98	Limited	Biomarker	[24]
Fetal growth restriction	DIS5WEJ5	Limited	Biomarker	[25]
Neuralgia	DISWO58J	Limited	Biomarker	[15]
Wolfram syndrome 1	DISC2P61	Limited	Biomarker	[26]

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 Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[27]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[28]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[30]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[31]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[32]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Plasma membrane calcium-transporting ATPase 2 (ATP2B2).	[35]

References

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• [2] Calcium-ATPase activity in erythrocyte ghosts from patients with familial benign hypercalcaemia.Scand J Clin Lab Invest. 1985 Jun;45(4):349-53. doi: 10.3109/00365518509161018.
• [3] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [4] The evidence for association of ATP2B2 polymorphisms with autism in Chinese Han population.PLoS One. 2013 Apr 19;8(4):e61021. doi: 10.1371/journal.pone.0061021. Print 2013.
• [5] Converging evidence for an association of ATP2B2 allelic variants with autism in male subjects.Biol Psychiatry. 2011 Nov 1;70(9):880-7. doi: 10.1016/j.biopsych.2011.05.020. Epub 2011 Jul 14.
• [6] De novo and inherited loss-of-function variants of ATP2B2 are associated with rapidly progressive hearing impairment. Hum Genet. 2019 Jan;138(1):61-72. doi: 10.1007/s00439-018-1965-1. Epub 2018 Dec 8.
• [7] Differential expression of PMCA2 mRNA isoforms in a cohort of Spanish patients with breast tumor types.Oncol Lett. 2018 Dec;16(6):6950-6959. doi: 10.3892/ol.2018.9540. Epub 2018 Oct 2.
• [8] Plasma membrane Ca-ATPase isoform expression in human cataractous lenses compared to age-matched clear lenses.Ophthalmic Res. 2008;40(2):86-93. doi: 10.1159/000113886. Epub 2008 Jan 25.
• [9] Survival strategies for mouse cerebellar Purkinje neurons lacking PMCA2.Neurosci Lett. 2018 Jan 10;663:25-28. doi: 10.1016/j.neulet.2017.09.045.
• [10] Modification of human hearing loss by plasma-membrane calcium pump PMCA2. N Engl J Med. 2005 Apr 14;352(15):1557-64. doi: 10.1056/NEJMoa043899.
• [11] Reduced expression of PMCA1 is associated with increased blood pressure with age which is preceded by remodelling of resistance arteries.Aging Cell. 2017 Oct;16(5):1104-1113. doi: 10.1111/acel.12637. Epub 2017 Aug 9.
• [12] Expression of calcium pumps is differentially regulated by histone deacetylase inhibitors and estrogen receptor alpha in breast cancer cells.BMC Cancer. 2018 Oct 23;18(1):1029. doi: 10.1186/s12885-018-4945-x.
• [13] Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2).Br J Cancer. 2020 Jan;122(2):266-278. doi: 10.1038/s41416-019-0675-3. Epub 2019 Dec 10.
• [14] Contribution of Plasma Membrane Calcium ATPases to neuronal maladaptive responses: Focus on spinal nociceptive mechanisms and neurodegeneration.Neurosci Lett. 2018 Jan 10;663:60-65. doi: 10.1016/j.neulet.2017.08.003. Epub 2017 Aug 2.
• [15] Pathological pain processing in mouse models of multiple sclerosis and spinal cord injury: contribution of plasma membrane calcium ATPase 2 (PMCA2).J Neuroinflammation. 2019 Nov 8;16(1):207. doi: 10.1186/s12974-019-1585-2.
• [16] Genome-wide association meta-analysis of age at first cannabis use.Addiction. 2018 Nov;113(11):2073-2086. doi: 10.1111/add.14368. Epub 2018 Aug 19.
• [17] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.Mol Autism. 2017 May 22;8:21. doi: 10.1186/s13229-017-0137-9. eCollection 2017.
• [18] The Na(+)/Ca(2+) exchanger and the Plasma Membrane Ca(2+)-ATPase in -cell function and diabetes.Neurosci Lett. 2018 Jan 10;663:72-78. doi: 10.1016/j.neulet.2017.08.009. Epub 2017 Aug 3.
• [19] One-megabase yeast artificial chromosome and 400-kilobase cosmid-phage contigs containing the von Hippel-Lindau tumor suppressor and Ca(2+)-transporting adenosine triphosphatase isoform 2 genes.Cancer Res. 1994 May 1;54(9):2486-91.
• [20] Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease.Mol Psychiatry. 2017 May;22(5):711-723. doi: 10.1038/mp.2016.148. Epub 2016 Sep 13.
• [21] 3p-- syndrome defines a hearing loss locus in 3p25.3.Hear Res. 2007 Feb;224(1-2):51-60. doi: 10.1016/j.heares.2006.11.006. Epub 2007 Jan 8.
• [22] PMCA2 silencing potentiates MDA-MB-231 breast cancer cell death initiated with the Bcl-2 inhibitor ABT-263.Biochem Biophys Res Commun. 2016 Sep 30;478(4):1792-7. doi: 10.1016/j.bbrc.2016.09.030. Epub 2016 Sep 7.
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• [24] Combined SSCP and heteroduplex analysis of the human plasma membrane Ca(2+)-ATPase isoform 1 in patients with essential hypertension.Biochem Biophys Res Commun. 1999 Aug 2;261(2):515-20. doi: 10.1006/bbrc.1999.1064.
• [25] Mechanisms Underpinning Adaptations in Placental Calcium Transport in Normal Mice and Those With Fetal Growth Restriction.Front Endocrinol (Lausanne). 2018 Nov 20;9:671. doi: 10.3389/fendo.2018.00671. eCollection 2018.
• [26] In search of the DFNA11 myosin VIIA low- and mid-frequency auditory genetic modifier.Otol Neurotol. 2008 Sep;29(6):860-7. doi: 10.1097/MAO.0b013e3181825651.
• [27] 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.
• [28] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [29] 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.
• [30] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [31] 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.
• [32] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [33] 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.
• [34] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [35] 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.