Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWFD3SI)

DOT Name	Homer protein homolog 1 (HOMER1)
Synonyms	Homer-1
Gene Name	HOMER1
Related Disease	Alzheimer disease ( ) Autism ( ) Cerebellar ataxia ( ) Drug dependence ( ) Epilepsy ( ) Hemangioma ( ) Hepatitis B virus infection ( ) Huntington disease ( ) Intrahepatic cholangiocarcinoma ( ) Major depressive disorder ( ) Mental disorder ( ) Parkinson disease ( ) Plasma cell myeloma ( ) Schizophrenia ( ) Substance abuse ( ) Varicose veins ( ) Hepatocellular carcinoma ( ) High blood pressure ( ) Stroke ( ) Amyotrophic lateral sclerosis ( ) Anxiety ( ) Anxiety disorder ( ) Bipolar disorder ( ) Cocaine addiction ( ) Depression ( ) Non-insulin dependent diabetes ( ) Type-1/2 diabetes ( )
UniProt ID	HOME1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF00568
Sequence	MGEQPIFSTRAHVFQIDPNTKKNWVPTSKHAVTVSYFYDSTRNVYRIISLDGSKAIINST ITPNMTFTKTSQKFGQWADSRANTVYGLGFSSEHHLSKFAEKFQEFKEAARLAKEKSQEK MELTSTPSQESAGGDLQSPLTPESINGTDDERTPDVTQNSEPRAEPTQNALPFSHSSAIS KHWEAELATLKGNNAKLTAALLESTANVKQWKQQLAAYQEEAERLHKRVTELECVSSQAN AVHTHKTELNQTIQELEETLKLKEEEIERLKQEIDNARELQEQRDSLTQKLQEVEIRNKD LEGQLSDLEQRLEKSQNEQEAFRNNLKTLLEILDGKIFELTELRDNLAKLLECS
Function	Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. May also couple GRM1 to PI3 kinase through its interaction with AGAP2. Isoform 1 regulates the trafficking and surface expression of GRM5. Isoform 3 acts as a natural dominant negative, in dynamic competition with constitutively expressed isoform 1 to regulate synaptic metabotropic glutamate function. Isoform 3, may be involved in the structural changes that occur at synapses during long-lasting neuronal plasticity and development. Forms a high-order complex with SHANK1, which in turn is necessary for the structural and functional integrity of dendritic spines. Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA.
KEGG Pathway	FoxO sig.ling pathway (hsa04068 ) Glutamatergic sy.pse (hsa04724 )
Reactome Pathway	Neurexins and neuroligins (R-HSA-6794361 )

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Autism	DISV4V1Z	Strong	Genetic Variation	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[3]
Drug dependence	DIS9IXRC	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[5]
Hemangioma	DISDCGAG	Strong	Biomarker	[6]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[7]
Huntington disease	DISQPLA4	Strong	Biomarker	[8]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[9]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[10]
Mental disorder	DIS3J5R8	Strong	Altered Expression	[11]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[12]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[14]
Substance abuse	DIS327VW	Strong	Genetic Variation	[15]
Varicose veins	DISIMBN2	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[17]
High blood pressure	DISY2OHH	moderate	Altered Expression	[18]
Stroke	DISX6UHX	moderate	Biomarker	[19]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[20]
Anxiety	DISIJDBA	Limited	Biomarker	[21]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[21]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[22]
Cocaine addiction	DISHTRXG	Limited	Biomarker	[23]
Depression	DIS3XJ69	Limited	Biomarker	[24]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[25]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[25]
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⏷ Show the Full List of 27 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cocaine	DMSOX7I	Approved	Homer protein homolog 1 (HOMER1) increases the response to substance of Cocaine.	[15]
Vinblastine	DM5TVS3	Approved	Homer protein homolog 1 (HOMER1) affects the response to substance of Vinblastine.	[43]
Levodopa	DMN3E57	Approved	Homer protein homolog 1 (HOMER1) affects the response to substance of Levodopa.	[12]
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16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Homer protein homolog 1 (HOMER1).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homer protein homolog 1 (HOMER1).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homer protein homolog 1 (HOMER1).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Homer protein homolog 1 (HOMER1).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homer protein homolog 1 (HOMER1).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Homer protein homolog 1 (HOMER1).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Homer protein homolog 1 (HOMER1).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Homer protein homolog 1 (HOMER1).	[34]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Homer protein homolog 1 (HOMER1).	[35]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Homer protein homolog 1 (HOMER1).	[36]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Homer protein homolog 1 (HOMER1).	[37]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Homer protein homolog 1 (HOMER1).	[38]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Homer protein homolog 1 (HOMER1).	[36]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Homer protein homolog 1 (HOMER1).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Homer protein homolog 1 (HOMER1).	[40]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Homer protein homolog 1 (HOMER1).	[41]
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⏷ Show the Full List of 16 Drug(s)

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Homer protein homolog 1 (HOMER1).	[33]
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References

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2	High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.PLoS One. 2012;7(4):e35003. doi: 10.1371/journal.pone.0035003. Epub 2012 Apr 27.
3	Neurochondrin Antibody Serum Positivity in Three Cases of Autoimmune Cerebellar Ataxia.Cerebellum. 2019 Dec;18(6):1137-1142. doi: 10.1007/s12311-019-01048-y.
4	Behavioral and Neurochemical Phenotyping of Mice Incapable of Homer1a Induction.Front Behav Neurosci. 2017 Nov 1;11:208. doi: 10.3389/fnbeh.2017.00208. eCollection 2017.
5	Neuronal PAS domain protein 4 (Npas4) controls neuronal homeostasis in pentylenetetrazole-induced epilepsy through the induction of Homer1a.J Neurochem. 2018 Apr;145(1):19-33. doi: 10.1111/jnc.14274. Epub 2017 Dec 28.
6	Potential role of Homer-2a on cutaneous vascular anomaly.J Korean Med Sci. 2002 Oct;17(5):636-40. doi: 10.3346/jkms.2002.17.5.636.
7	Clinical and Diagnostic Significance of Homer1 in hepatitis B virus-induced Hepatocellular Carcinoma.J Cancer. 2018 Jan 11;9(4):683-689. doi: 10.7150/jca.22279. eCollection 2018.
8	The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease.Neurobiol Dis. 2017 Jan;97(Pt A):46-59. doi: 10.1016/j.nbd.2016.10.006. Epub 2016 Nov 3.
9	Identification of Homer1 as a potential prognostic marker for intrahepatic cholangiocarcinoma.Asian Pac J Cancer Prev. 2014;15(7):3299-304. doi: 10.7314/apjcp.2014.15.7.3299.
10	Resequencing three candidate genes discovers seven potentially deleterious variants susceptibility to major depressive disorder and suicide attempts in Chinese.Gene. 2017 Mar 1;603:34-41. doi: 10.1016/j.gene.2016.12.006. Epub 2016 Dec 10.
11	Homer1a protein expression in schizophrenia, bipolar disorder, and major depression.J Neural Transm (Vienna). 2017 Oct;124(10):1261-1273. doi: 10.1007/s00702-017-1776-x. Epub 2017 Aug 16.
12	Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients. Pharmacogenomics J. 2014 Jun;14(3):289-94. doi: 10.1038/tpj.2013.37. Epub 2013 Oct 15.
13	Cell adhesion downregulates the expression of Homer1b/c and contributes to drug resistance in multiple myeloma cells.Oncol Rep. 2016 Mar;35(3):1875-83. doi: 10.3892/or.2015.4532. Epub 2015 Dec 29.
14	A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia.J Psychiatry Neurosci. 2018 Mar;43(2):102-110. doi: 10.1503/jpn.170077. Epub 2017 Oct 6.
15	Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population. Psychiatr Genet. 2005 Dec;15(4):277-83. doi: 10.1097/00041444-200512000-00010.
16	Homer1 (VesL-1) in the rat esophagus: focus on myenteric plexus and neuromuscular junction.Histochem Cell Biol. 2017 Aug;148(2):189-206. doi: 10.1007/s00418-017-1555-7. Epub 2017 Mar 23.
17	Glycolysis gene expression profilings screen for prognostic risk signature of hepatocellular carcinoma.Aging (Albany NY). 2019 Dec 2;11(23):10861-10882. doi: 10.18632/aging.102489. Epub 2019 Dec 2.
18	Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment.Geroscience. 2017 Aug;39(4):385-406. doi: 10.1007/s11357-017-9981-y. Epub 2017 Jun 29.
19	Diagnostic Potential of Differentially Expressed Homer1 and Homer2 in Ischemic Stroke.Cell Physiol Biochem. 2016;39(6):2353-2363. doi: 10.1159/000447927. Epub 2016 Nov 11.
20	Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid.Int J Mol Sci. 2016 Dec 17;17(12):2129. doi: 10.3390/ijms17122129.
21	Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia.Genes Brain Behav. 2005 Jul;4(5):273-88. doi: 10.1111/j.1601-183X.2005.00120.x.
22	A Homer 1 gene variant influences brain structure and function, lithium effects on white matter, and antidepressant response in bipolar disorder: A multimodal genetic imaging study.Prog Neuropsychopharmacol Biol Psychiatry. 2018 Feb 2;81:88-95. doi: 10.1016/j.pnpbp.2017.10.011. Epub 2017 Oct 27.
23	Homer isoforms differentially regulate cocaine-induced neuroplasticity.Neuropsychopharmacology. 2006 Apr;31(4):768-77. doi: 10.1038/sj.npp.1300890.
24	Enhanced adenosine A(1) receptor and Homer1a expression in hippocampus modulates the resilience to stress-induced depression-like behavior.Neuropharmacology. 2020 Jan 1;162:107834. doi: 10.1016/j.neuropharm.2019.107834. Epub 2019 Nov 1.
25	The Impact of Small RNA Interference Against Homer1 on Rats with Type 2 Diabetes and ERK Phosphorylation.Cell Biochem Biophys. 2015 Dec;73(3):597-601. doi: 10.1007/s12013-015-0657-x.
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	Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
28	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.
29	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.
30	Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
31	17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
32	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.
33	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.
34	Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
35	THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
36	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
37	Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
38	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.
39	Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
40	Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
41	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
42	Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population. Psychiatr Genet. 2005 Dec;15(4):277-83. doi: 10.1097/00041444-200512000-00010.
43	Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
44	Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson's disease patients. Pharmacogenomics J. 2014 Jun;14(3):289-94. doi: 10.1038/tpj.2013.37. Epub 2013 Oct 15.