Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJGX19T)

• DOT Name: Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A)
• Synonyms: CaM kinase II subunit alpha; CaMK-II subunit alpha; EC 2.7.11.17
• Gene Name: CAMK2A
• Related Disease:
  Angelman syndrome
  Alcohol dependence
  Alzheimer disease
  Autism spectrum disorder
  Bipolar disorder
  Bone osteosarcoma
  Bronchopulmonary dysplasia
  Conduct disorder
  Depression
  Eye disorder
  Huntington disease
  Intellectual disability, autosomal dominant 40
  Intellectual disability, autosomal dominant 53
  Major depressive disorder
  Movement disorder
  Non-insulin dependent diabetes
  Obesity
  Osteosarcoma
  Schizophrenia
  Squamous cell carcinoma
  Ventricular septal defect
  Wilson disease
  Treacher-Collins syndrome
  Autosomal dominant non-syndromic intellectual disability
  Cocaine addiction
  Frontotemporal dementia
  Glioblastoma multiforme
  High blood pressure
  Inflammatory bowel disease
  Intellectual disability
  Intellectual disability, autosomal recessive 63
  Lewy body dementia
  Ulcerative colitis
• UniProt ID: KCC2A_HUMAN
• PDB ID: 2VZ6; 3SOA; 5IG3; 6OF8; 6VZK; 6W4O; 6W4P; 6X5G; 6X5Q; 7KL0; 7KL1; 7KL2; 7REC; 7UIQ; 7UIR; 7UIS; 7UJP; 7UJQ; 7UJR; 7UJS; 7UJT
• EC Number: 2.7.11.17
• Pfam ID: PF08332 ; PF00069
• Sequence:
  MATITCTRFTEEYQLFEELGKGAFSVVRRCVKVLAGQEYAAKIINTKKLSARDHQKLERE
  ARICRLLKHPNIVRLHDSISEEGHHYLIFDLVTGGELFEDIVAREYYSEADASHCIQQIL
  EAVLHCHQMGVVHRDLKPENLLLASKLKGAAVKLADFGLAIEVEGEQQAWFGFAGTPGYL
  SPEVLRKDPYGKPVDLWACGVILYILLVGYPPFWDEDQHRLYQQIKAGAYDFPSPEWDTV
  TPEAKDLINKMLTINPSKRITAAEALKHPWISHRSTVASCMHRQETVDCLKKFNARRKLK
  GAILTTMLATRNFSGGKSGGNKKSDGVKESSESTNTTIEDEDTKVRKQEIIKVTEQLIEA
  ISNGDFESYTKMCDPGMTAFEPEALGNLVEGLDFHRFYFENLWSRNSKPVHTTILNPHIH
  LMGDESACIAYIRITQYLDAGGIPRTAQSEETRVWHRRDGKWQIVHFHRSGAPSVLPH
• Function: Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term potentiation. Member of the NMDAR signaling complex in excitatory synapses, it regulates NMDAR-dependent potentiation of the AMPAR and therefore excitatory synaptic transmission. Regulates dendritic spine development. Also regulates the migration of developing neurons. Phosphorylates the transcription factor FOXO3 to activate its transcriptional activity. Phosphorylates the transcription factor ETS1 in response to calcium signaling, thereby decreasing ETS1 affinity for DNA. In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway. In response to interferon-beta (IFN-beta) stimulation, stimulates the JAK-STAT signaling pathway. Acts as a negative regulator of 2-arachidonoylglycerol (2-AG)-mediated synaptic signaling via modulation of DAGLA activity.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  HIF-1 sig.ling pathway (hsa04066)
  Oocyte meiosis (hsa04114)
  Efferocytosis (hsa04148)
  Necroptosis (hsa04217)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Neurotrophin sig.ling pathway (hsa04722)
  Cholinergic sy.pse (hsa04725)
  Dopaminergic sy.pse (hsa04728)
  Olfactory transduction (hsa04740)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Melanogenesis (hsa04916)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Aldosterone synthesis and secretion (hsa04925)
  Cushing syndrome (hsa04934)
  Gastric acid secretion (hsa04971)
  Parkinson disease (hsa05012)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Amphetamine addiction (hsa05031)
  Tuberculosis (hsa05152)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Glioma (hsa05214)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  HSF1-dependent transactivation (R-HSA-3371571)
  Trafficking of AMPA receptors (R-HSA-399719)
  Ca2+ pathway (R-HSA-4086398)
  Unblocking of NMDA receptors, glutamate binding and activation (R-HSA-438066)
  Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982)
  Phase 0 - rapid depolarisation (R-HSA-5576892)
  Ion homeostasis (R-HSA-5578775)
  RAF activation (R-HSA-5673000)
  RAF/MAP kinase cascade (R-HSA-5673001)
  Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946)
  Signaling by BRAF and RAF1 fusions (R-HSA-6802952)
  Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955)
  Interferon gamma signaling (R-HSA-877300)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  Ion transport by P-type ATPases (R-HSA-936837)
  Assembly and cell surface presentation of NMDA receptors (R-HSA-9609736)
  Negative regulation of NMDA receptor-mediated neuronal transmission (R-HSA-9617324)
  Long-term potentiation (R-HSA-9620244)
  Signaling downstream of RAS mutants (R-HSA-9649948)
  Signaling by RAF1 mutants (R-HSA-9656223)
  CaMK IV-mediated phosphorylation of CREB (R-HSA-111932)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angelman syndrome	DIS4QVXO	Definitive	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[6]
Bronchopulmonary dysplasia	DISO0BY5	Strong	Biomarker	[5]
Conduct disorder	DISOLUZ1	Strong	Genetic Variation	[7]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Eye disorder	DISB52BH	Strong	Genetic Variation	[8]
Huntington disease	DISQPLA4	Strong	Biomarker	[9]
Intellectual disability, autosomal dominant 40	DISAI0IH	Strong	Autosomal dominant	[8]
Intellectual disability, autosomal dominant 53	DISYR1KX	Strong	Autosomal dominant	[10]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[11]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[12]
Obesity	DIS47Y1K	Strong	Genetic Variation	[13]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[14]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[15]
Ventricular septal defect	DISICO41	Strong	CausalMutation	[8]
Wilson disease	DISVS9H7	Strong	Biomarker	[16]
Treacher-Collins syndrome	DIS2GXZ1	moderate	Genetic Variation	[17]
Autosomal dominant non-syndromic intellectual disability	DISD6L06	Supportive	Autosomal dominant	[8]
Cocaine addiction	DISHTRXG	Limited	Genetic Variation	[18]
Frontotemporal dementia	DISKYHXL	Limited	Altered Expression	[19]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[20]
High blood pressure	DISY2OHH	Limited	Biomarker	[21]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[22]
Intellectual disability	DISMBNXP	Limited	Biomarker	[23]
Intellectual disability, autosomal recessive 63	DISJ5VJQ	Limited	Autosomal recessive	[24]
Lewy body dementia	DISAE66J	Limited	Altered Expression	[25]
Ulcerative colitis	DIS8K27O	Limited	Genetic Variation	[22]

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/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[26]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[27]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[29]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[30]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[32]
AMEP	DMFELMQ	Phase 1	AMEP decreases the expression of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[33]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Calcium/calmodulin-dependent protein kinase type II subunit alpha (CAMK2A).	[33]

References

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• [2] CaMKII autophosphorylation controls the establishment of alcohol drinking behavior.Neuropsychopharmacology. 2013 Aug;38(9):1636-47. doi: 10.1038/npp.2013.60. Epub 2013 Mar 4.
• [3] A Comprehensive Analysis of the CaMK2A Gene and Susceptibility to Alzheimer's Disease in the Han Chinese Population.Front Aging Neurosci. 2019 Apr 11;11:84. doi: 10.3389/fnagi.2019.00084. eCollection 2019.
• [4] Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities.J Neural Transm (Vienna). 2018 Feb;125(2):259-271. doi: 10.1007/s00702-017-1813-9. Epub 2017 Nov 16.
• [5] Interactome Analyses implicated CAMK2A in the genetic predisposition and pharmacological mechanism of Bipolar Disorder.J Psychiatr Res. 2019 Aug;115:165-175. doi: 10.1016/j.jpsychires.2019.05.024. Epub 2019 May 25.
• [6] Inhibition of CaMKII Activity Enhances Antitumor Effect of Fullerene C60 Nanocrystals by Suppression of Autophagic Degradation.Adv Sci (Weinh). 2019 Feb 10;6(8):1801233. doi: 10.1002/advs.201801233. eCollection 2019 Apr 17.
• [7] Association of ADAM10 and CAMK2A polymorphisms with conduct disorder: evidence from family-based studies.J Abnorm Child Psychol. 2011 Aug;39(6):773-82. doi: 10.1007/s10802-011-9524-4.
• [8] De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. Am J Hum Genet. 2017 Nov 2;101(5):768-788. doi: 10.1016/j.ajhg.2017.10.003.
• [9] Differential electrophysiological and morphological alterations of thalamostriatal and corticostriatal projections in the R6/2 mouse model of Huntington's disease.Neurobiol Dis. 2017 Dec;108:29-44. doi: 10.1016/j.nbd.2017.07.020. Epub 2017 Jul 27.
• [10] Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992 Jul 10;257(5067):206-11. doi: 10.1126/science.1321493.
• [11] Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains.Neurosci Res. 2008 Feb;60(2):184-91. doi: 10.1016/j.neures.2007.10.010. Epub 2007 Nov 6.
• [12] Arsenic is more potent than cadmium or manganese in disrupting the INS-1 beta cell microRNA landscape.Arch Toxicol. 2019 Nov;93(11):3099-3109. doi: 10.1007/s00204-019-02574-8. Epub 2019 Sep 25.
• [13] Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism.Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16064-9. doi: 10.1073/pnas.0405041101. Epub 2004 Nov 1.
• [14] Amphetamine sensitization elevates CaMKIIbeta mRNA.Synapse. 2007 Oct;61(10):827-34. doi: 10.1002/syn.20429.
• [15] Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells.J Biol Chem. 2006 May 19;281(20):14026-40. doi: 10.1074/jbc.M507734200. Epub 2006 Mar 24.
• [16] The early molecular processes underlying the neurological manifestations of an animal model of Wilson's disease.Metallomics. 2013 May;5(5):532-40. doi: 10.1039/c3mt20243g. Epub 2013 Mar 21.
• [17] Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability.Eur J Hum Genet. 2014 Jan;22(1):52-6. doi: 10.1038/ejhg.2013.98. Epub 2013 May 22.
• [18] CaMKII controls the establishment of cocaine's reinforcing effects in mice and humans.Transl Psychiatry. 2014 Oct 7;4(10):e457. doi: 10.1038/tp.2014.97.
• [19] An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice.Hum Mol Genet. 2015 Dec 20;24(25):7241-54. doi: 10.1093/hmg/ddv424. Epub 2015 Oct 16.
• [20] A 63 signature genes prediction system is effective for glioblastoma prognosis.Int J Mol Med. 2018 Apr;41(4):2070-2078. doi: 10.3892/ijmm.2018.3422. Epub 2018 Jan 25.
• [21] Redox-sensitive calcium/calmodulin-dependent protein kinase II in angiotensin II intra-neuronal signaling and hypertension.Redox Biol. 2019 Oct;27:101230. doi: 10.1016/j.redox.2019.101230. Epub 2019 May 30.
• [22] Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.Nat Genet. 2017 Feb;49(2):256-261. doi: 10.1038/ng.3760. Epub 2017 Jan 9.
• [23] De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders.Ann Clin Transl Neurol. 2018 Jan 29;5(3):280-296. doi: 10.1002/acn3.528. eCollection 2018 Mar.
• [24] 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.
• [25] Behavioural deficits in transgenic mice expressing human truncated (1-120 amino acid) alpha-synuclein.Exp Neurol. 2015 Feb;264:8-13. doi: 10.1016/j.expneurol.2014.11.003. Epub 2014 Nov 20.
• [26] 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.
• [27] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [28] 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.
• [29] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [30] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [31] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [32] Effect of benzo[a]pyrene on proliferation and metastasis of oral squamous cell carcinoma cells: A transcriptome analysis based on RNA-seq. Environ Toxicol. 2022 Nov;37(11):2589-2604. doi: 10.1002/tox.23621. Epub 2022 Jul 23.
• [33] Use of human neuroblastoma SH-SY5Y cells to evaluate glyphosate-induced effects on oxidative stress, neuronal development and cell death signaling pathways. Environ Int. 2020 Feb;135:105414. doi: 10.1016/j.envint.2019.105414. Epub 2019 Dec 23.