Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDQA90X)

• DOT Name: Regulator of G-protein signaling 7 (RGS7)
• Synonyms: RGS7
• Gene Name: RGS7
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Melanoma
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Creutzfeldt Jacob disease
  Depression
  Intellectual disability
  Neuralgia
  Non-insulin dependent diabetes
  Panic disorder
  Stroke
  Uterine fibroids
  Acute myelogenous leukaemia
  Leiomyomatosis
  Neoplasm
• UniProt ID: RGS7_HUMAN
• PDB ID: 2A72; 2D9J; 7EWP; 7EWR; 7SHF
• Pfam ID: PF00610 ; PF00631 ; PF00615 ; PF18148
• Sequence:
  MAQGNNYGQTSNGVADESPNMLVYRKMEDVIARMQDEKNGIPIRTVKSFLSKIPSVFSGS
  DIVQWLIKNLTIEDPVEALHLGTLMAAHGYFFPISDHVLTLKDDGTFYRFQTPYFWPSNC
  WEPENTDYAVYLCKRTMQNKARLELADYEAESLARLQRAFARKWEFIFMQAEAQAKVDKK
  RDKIERKILDSQERAFWDVHRPVPGCVNTTEVDIKKSSRMRNPHKTRKSVYGLQNDIRSH
  SPTHTPTPETKPPTEDELQQQIKYWQIQLDRHRLKMSKVADSLLSYTEQYLEYDPFLLPP
  DPSNPWLSDDTTFWELEASKEPSQQRVKRWGFGMDEALKDPVGREQFLKFLESEFSSENL
  RFWLAVEDLKKRPIKEVPSRVQEIWQEFLAPGAPSAINLDSKSYDKTTQNVKEPGRYTFE
  DAQEHIYKLMKSDSYPRFIRSSAYQELLQAKKKSGNSMDRRTSFEKFAQNVGRNIPIFPC
  HKNCTPTLRASTNLL
• Function: GTPase activator component of the RGS7-GNB5 complex that regulates G protein-coupled receptor signaling cascades. The RGS7-GNB5 complex acts as an inhibitor signal transduction by promoting the GTPase activity of G protein alpha subunits, such as GNAO1, thereby driving them into their inactive GDP-bound form. May play a role in synaptic vesicle exocytosis (Probable). Glycine-dependent regulation of the RGS7-GNB5 complex by GPR158 affects mood and cognition via its ability to regulate neuronal excitability in L2/L3 pyramidal neurons of the prefrontal cortex. Modulates the activity of potassium channels that are activated by GNAO1 in response to muscarinic acetylcholine receptor M2/CHRM2 signaling.
• Reactome Pathway:
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Definitive	Biomarker	[1]
Melanoma	DIS1RRCY	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[4]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Genetic Variation	[5]
Depression	DIS3XJ69	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	Strong	Biomarker	[7]
Neuralgia	DISWO58J	Strong	Altered Expression	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[9]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[10]
Stroke	DISX6UHX	Strong	Biomarker	[11]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[12]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[13]
Leiomyomatosis	DISNOOME	Limited	Genetic Variation	[14]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[2]

9 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 Regulator of G-protein signaling 7 (RGS7).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Regulator of G-protein signaling 7 (RGS7).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Regulator of G-protein signaling 7 (RGS7).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Regulator of G-protein signaling 7 (RGS7).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Regulator of G-protein signaling 7 (RGS7).	[20]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Regulator of G-protein signaling 7 (RGS7).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Regulator of G-protein signaling 7 (RGS7).	[22]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Regulator of G-protein signaling 7 (RGS7).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Regulator of G-protein signaling 7 (RGS7).	[26]

3 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 Regulator of G-protein signaling 7 (RGS7).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Regulator of G-protein signaling 7 (RGS7).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Regulator of G-protein signaling 7 (RGS7).	[25]

References

• [1] Interaction between RGS7 and polycystin.Proc Natl Acad Sci U S A. 1999 May 25;96(11):6371-6. doi: 10.1073/pnas.96.11.6371.
• [2] RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells.Sci Rep. 2018 Jan 12;8(1):653. doi: 10.1038/s41598-017-18851-4.
• [3] Structural organization of a major neuronal G protein regulator, the RGS7-G5-R7BP complex.Elife. 2018 Dec 12;7:e42150. doi: 10.7554/eLife.42150.
• [4] Association of frequent genetic variants in platelet activation pathway genes with large-vessel ischemic stroke in Polish population.Platelets. 2017 Jan;28(1):66-73. doi: 10.1080/09537104.2016.1203404. Epub 2016 Aug 17.
• [5] Genome-wide study links MTMR7 gene to variant Creutzfeldt-Jakob risk.Neurobiol Aging. 2012 Jul;33(7):1487.e21-8. doi: 10.1016/j.neurobiolaging.2011.10.011. Epub 2011 Dec 2.
• [6] Homeostatic cAMP regulation by the RGS7 complex controls depression-related behaviors.Neuropsychopharmacology. 2019 Feb;44(3):642-653. doi: 10.1038/s41386-018-0238-y. Epub 2018 Oct 11.
• [7] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [8] Inflammation-associated regulation of RGS in astrocytes and putative implication in neuropathic pain.J Neuroinflammation. 2017 Oct 27;14(1):209. doi: 10.1186/s12974-017-0971-x.
• [9] Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.PLoS Genet. 2014 Aug 7;10(8):e1004517. doi: 10.1371/journal.pgen.1004517. eCollection 2014 Aug.
• [10] Association analysis of Rgs7 variants with panic disorder.J Neural Transm (Vienna). 2009 Nov;116(11):1523-8. doi: 10.1007/s00702-008-0097-5. Epub 2008 Sep 2.
• [11] Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.Nat Genet. 2018 Apr;50(4):524-537. doi: 10.1038/s41588-018-0058-3. Epub 2018 Mar 12.
• [12] Fine mapping of the uterine leiomyoma locus on 1q43 close to a lncRNA in the RGS7-FH interval.Endocr Relat Cancer. 2015 Aug;22(4):633-43. doi: 10.1530/ERC-15-0208. Epub 2015 Jun 25.
• [13] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [14] Germline deletions of EXO1 do not cause colorectal tumors and lesions which are null for EXO1 do not have microsatellite instability.Cancer Genet Cytogenet. 2003 Dec;147(2):121-7. doi: 10.1016/s0165-4608(03)00196-1.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] 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.
• [19] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [20] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [21] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [22] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [23] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [24] 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.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.