Details of Drug Off-Target (DOT)

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

• DOT Name: Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2)
• Synonyms: Adenylate cyclase-inhibiting G alpha protein
• Gene Name: GNAI2
• Related Disease:
  Carcinoma
  Neoplasm
  Acromegaly
  Arrhythmia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colitis
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Essential hypertension
  Hepatocellular carcinoma
  High blood pressure
  Inflammatory bowel disease
  Intellectual disability
  Lung cancer
  Lung carcinoma
  Periventricular nodular heterotopia
  Postmenopausal osteoporosis
  Atrioventricular block
  Undifferentiated carcinoma
  Advanced cancer
  Clear cell adenocarcinoma
  Epithelial ovarian cancer
  Matthew-Wood syndrome
  Neurodevelopmental disorder
  Ovarian cancer
  Ovarian neoplasm
  Ventricular tachycardia, familial
• UniProt ID: GNAI2_HUMAN
• PDB ID: 6D9H; 7F8V; 7LD3; 7LD4; 7WV9; 7WVV; 7WVW; 7WVX; 7WVY; 7XXI; 7YJ4; 7YK6; 7YK7
• Pfam ID: PF00503
• Sequence:
  MGCTVSAEDKAAAERSKMIDKNLREDGEKAAREVKLLLLGAGESGKSTIVKQMKIIHEDG
  YSEEECRQYRAVVYSNTIQSIMAIVKAMGNLQIDFADPSRADDARQLFALSCTAEEQGVL
  PDDLSGVIRRLWADHGVQACFGRSREYQLNDSAAYYLNDLERIAQSDYIPTQQDVLRTRV
  KTTGIVETHFTFKDLHFKMFDVGGQRSERKKWIHCFEGVTAIIFCVALSAYDLVLAEDEE
  MNRMHESMKLFDSICNNKWFTDTSIILFLNKKDLFEEKITHSPLTICFPEYTGANKYDEA
  ASYIQSKFEDLNKRKDTKEIYTHFTCATDTKNVQFVFDAVTDVIIKNNLKDCGLF
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. May play a role in cell division; [Isoform sGi2]: Regulates the cell surface density of dopamine receptors DRD2 by sequestrating them as an intracellular pool.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Sphingolipid sig.ling pathway (hsa04071)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Axon guidance (hsa04360)
  Apelin sig.ling pathway (hsa04371)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Leukocyte transendothelial migration (hsa04670)
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Oxytocin sig.ling pathway (hsa04921)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Relaxin sig.ling pathway (hsa04926)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Gastric acid secretion (hsa04971)
  Parkinson disease (hsa05012)
  Cocaine addiction (hsa05030)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Pertussis (hsa05133)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Human cytomegalovirus infection (hsa05163)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  ADP signalling through P2Y purinoceptor 12 (R-HSA-392170)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  G alpha (s) signalling events (R-HSA-418555)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Regulation of insulin secretion (R-HSA-422356)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  Adenylate cyclase inhibitory pathway (R-HSA-170670)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Acromegaly	DISCC73U	Strong	Genetic Variation	[3]
Arrhythmia	DISFF2NI	Strong	Therapeutic	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Colitis	DISAF7DD	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Genetic Variation	[7]
Colon carcinoma	DISJYKUO	Strong	Genetic Variation	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[6]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[10]
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[12]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Genetic Variation	[13]
Postmenopausal osteoporosis	DISS0RQZ	Strong	Biomarker	[14]
Atrioventricular block	DIS8YLE6	moderate	Biomarker	[15]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[6]
Clear cell adenocarcinoma	DISYUGHZ	Limited	Biomarker	[16]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[16]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[17]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[11]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[16]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[16]
Ventricular tachycardia, familial	DISYG7IE	No Known	Unknown	[18]

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 Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[25]
Selenium	DM25CGV	Approved	Selenium increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[26]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[27]
Nicotine	DMWX5CO	Approved	Nicotine increases the splicing of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[28]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[29]
Propofol	DMB4OLE	Approved	Propofol decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[30]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[31]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[34]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[37]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[38]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2).	[39]

References

• [1] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [2] Identification and experimental validation of G protein alpha inhibiting activity polypeptide 2 (GNAI2) as a microRNA-138 target in tongue squamous cell carcinoma.Hum Genet. 2011 Feb;129(2):189-97. doi: 10.1007/s00439-010-0915-3. Epub 2010 Nov 16.
• [3] Study of the multiple endocrine neoplasia type 1, growth hormone-releasing hormone receptor, Gs alpha, and Gi2 alpha genes in isolated familial acromegaly.J Clin Endocrinol Metab. 2001 Feb;86(2):542-4. doi: 10.1210/jcem.86.2.7218.
• [4] [Alteration of the expression of rat cardiac Galphaq/11 and Gialpha2 proteins during endothelin-1 pre-treatment].Sheng Li Xue Bao. 2000 Dec;52(6):459-62.
• [5] Expression profiling identifies genes that predict recurrence of breast cancer after adjuvant CMF-based chemotherapy.Breast Cancer Res Treat. 2009 Nov;118(1):45-56. doi: 10.1007/s10549-008-0207-y. Epub 2008 Oct 17.
• [6] GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by Blocking IL6 Signaling and Down-regulating Expression of GNAI2.Gastroenterology. 2019 Jun;156(8):2297-2312. doi: 10.1053/j.gastro.2019.02.040. Epub 2019 Mar 2.
• [7] Absence of GNAI2 codon 179 oncogene mutations in inflammatory bowel disease.Inflamm Bowel Dis. 2000 May;6(2):103-6. doi: 10.1097/00054725-200005000-00006.
• [8] The -318 C>G single-nucleotide polymorphism in GNAI2 gene promoter region impairs transcriptional activity through specific binding of Sp1 transcription factor and is associated with high blood pressure in Caucasians from Italy.J Am Soc Nephrol. 2006 Apr;17(4 Suppl 2):S115-9. doi: 10.1681/ASN.2005121340.
• [9] MicroRNA-30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma.Hepatology. 2010 Mar;51(3):846-56. doi: 10.1002/hep.23443.
• [10] GNAI2 polymorphic variance associates with salt sensitivity of blood pressure in the Genetic Epidemiology Network of Salt Sensitivity study.Physiol Genomics. 2018 Sep 1;50(9):724-725. doi: 10.1152/physiolgenomics.00141.2017. Epub 2018 Jun 15.
• [11] Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants.Genet Med. 2019 Nov;21(11):2504-2511. doi: 10.1038/s41436-019-0518-x. Epub 2019 Apr 30.
• [12] Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin.Oncogene. 1996 Mar 21;12(6):1289-97.
• [13] Role of a heterotrimeric G-protein, Gi2, in the corticogenesis: possible involvement in periventricular nodular heterotopia and intellectual disability.J Neurochem. 2017 Jan;140(1):82-95. doi: 10.1111/jnc.13878. Epub 2016 Nov 29.
• [14] Bioinformatics analysis of gene expression profiles in B cells of postmenopausal osteoporosis patients.Taiwan J Obstet Gynecol. 2017 Apr;56(2):165-170. doi: 10.1016/j.tjog.2016.04.038.
• [15] Endogenous RGS proteins modulate SA and AV nodal functions in isolated heart: implications for sick sinus syndrome and AV block.Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2532-9. doi: 10.1152/ajpheart.01391.2006. Epub 2007 Feb 2.
• [16] Suppression of GNAI2 message in ovarian cancer.J Ovarian Res. 2014 Jan 14;7:6. doi: 10.1186/1757-2215-7-6.
• [17] Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice.Gastroenterology. 2016 Dec;151(6):1218-1231. doi: 10.1053/j.gastro.2016.08.040. Epub 2016 Aug 28.
• [18] Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunitalphai2. J Clin Invest. 1998 Jun 15;101(12):2862-8. doi: 10.1172/JCI1582.
• [19] 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.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] 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.
• [22] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [23] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] 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.
• [26] 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.
• [27] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [28] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [29] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [30] Propofol suppresses proliferation, migration, invasion, and tumor growth of liver cancer cells via suppressing cancer susceptibility candidate 9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic target of rapamycin kinase axis. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271211065972. doi: 10.1177/09603271211065972.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [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] 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.
• [35] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [36] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [37] 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.
• [38] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [39] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.