Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA6HYBA)

• DOT Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3)
• Synonyms: Transducin beta chain 3
• Gene Name: GNB3
• Related Disease:
  Chronic kidney disease
  Thyroid tumor
  Acute myocardial infarction
  Adenoma
  Advanced cancer
  Age-related macular degeneration
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Bipolar disorder
  Breast neoplasm
  Cardiac failure
  Cholangiocarcinoma
  Congenital stationary night blindness 1H
  Congestive heart failure
  Coronary atherosclerosis
  Coronary heart disease
  Dyspepsia
  Gastric cancer
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Hepatitis
  Hepatitis C virus infection
  Liver cirrhosis
  Metastatic malignant neoplasm
  Mood disorder
  Polycystic ovarian syndrome
  Pulmonary disease
  Retinopathy
  Small lymphocytic lymphoma
  Stomach cancer
  Vesicoureteral reflux
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Thyroid gland carcinoma
  Type-1/2 diabetes
  Congenital stationary night blindness
  Neoplasm
  Nephropathy
  B-cell neoplasm
  Cardiomyopathy
  Cardiovascular disease
  Myopia
  Rheumatoid arthritis
  Stroke
  Type-1 diabetes
• UniProt ID: GBB3_HUMAN
• Pfam ID: PF00400
• Sequence:
  MGEMEQLRQEAEQLKKQIADARKACADVTLAELVSGLEVVGRVQMRTRRTLRGHLAKIYA
  MHWATDSKLLVSASQDGKLIVWDSYTTNKVHAIPLRSSWVMTCAYAPSGNFVACGGLDNM
  CSIYNLKSREGNVKVSRELSAHTGYLSCCRFLDDNNIVTSSGDTTCALWDIETGQQKTVF
  VGHTGDCMSLAVSPDFNLFISGACDASAKLWDVREGTCRQTFTGHESDINAICFFPNGEA
  ICTGSDDASCRLFDLRADQELICFSHESIICGITSVAFSLSGRLLFAGYDDFNCNVWDSM
  KSERVGILSGHDNRVSCLGVTADGMAVATGSWDSFLKIWN
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apelin sig.ling pathway (hsa04371)
  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)
  Taste transduction (hsa04742)
  Relaxin sig.ling pathway (hsa04926)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Glucagon signaling in metabolic regulation (R-HSA-163359)
  G-protein activation (R-HSA-202040)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771)
  ADP signalling through P2Y purinoceptor 12 (R-HSA-392170)
  G beta (R-HSA-392451)
  Prostacyclin signalling through prostacyclin receptor (R-HSA-392851)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  G beta (R-HSA-418217)
  G alpha (s) signalling events (R-HSA-418555)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Glucagon-type ligand receptors (R-HSA-420092)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  G beta (R-HSA-8964315)
  G beta (R-HSA-8964616)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Definitive	Genetic Variation	[1]
Thyroid tumor	DISLVKMD	Definitive	Genetic Variation	[2]
Acute myocardial infarction	DISE3HTG	Strong	Genetic Variation	[3]
Adenoma	DIS78ZEV	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Age-related macular degeneration	DIS0XS2C	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[7]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[8]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[8]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[9]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[10]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[11]
Cardiac failure	DISDC067	Strong	Genetic Variation	[12]
Cholangiocarcinoma	DIS71F6X	Strong	Genetic Variation	[13]
Congenital stationary night blindness 1H	DISFFSU2	Strong	Autosomal recessive	[14]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[12]
Coronary atherosclerosis	DISKNDYU	Strong	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[15]
Dyspepsia	DISYEEY6	Strong	Genetic Variation	[16]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[17]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[18]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[19]
Hepatitis	DISXXX35	Strong	Genetic Variation	[13]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[13]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[20]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[11]
Mood disorder	DISLVMWO	Strong	Biomarker	[21]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[22]
Pulmonary disease	DIS6060I	Strong	Biomarker	[23]
Retinopathy	DISB4B0F	Strong	Biomarker	[24]
Small lymphocytic lymphoma	DIS30POX	Strong	Genetic Variation	[25]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[17]
Vesicoureteral reflux	DISUL6SA	Strong	Genetic Variation	[26]
Prostate cancer	DISF190Y	moderate	Genetic Variation	[27]
Prostate carcinoma	DISMJPLE	moderate	Genetic Variation	[27]
Schizophrenia	DISSRV2N	moderate	Genetic Variation	[28]
Thyroid gland carcinoma	DISMNGZ0	moderate	Genetic Variation	[5]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[29]
Congenital stationary night blindness	DISX0CWK	Supportive	Autosomal dominant	[14]
Neoplasm	DISZKGEW	Disputed	Genetic Variation	[30]
Nephropathy	DISXWP4P	Disputed	Genetic Variation	[31]
B-cell neoplasm	DISVY326	Limited	Genetic Variation	[32]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[33]
Cardiovascular disease	DIS2IQDX	Limited	Genetic Variation	[34]
Myopia	DISK5S60	Limited	Genetic Variation	[35]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[36]
Stroke	DISX6UHX	Limited	Genetic Variation	[15]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[37]

This DOT Affected the Drug Response of 12 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) decreases the response to substance of Clozapine.	[47]
Nortriptyline	DM4KDYJ	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) decreases the response to substance of Nortriptyline.	[48]
Sibutramine	DMFJTDI	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the Lose weight ADR of Sibutramine.	[49]
Almogran	DM7I64Z	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Almogran.	[50]
Sumatriptan	DMVYXR8	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Sumatriptan.	[50]
Zolmitriptan	DM1IB4Q	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Zolmitriptan.	[50]
Eletriptan	DMW649X	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Eletriptan.	[50]
Frovatriptan	DM7RE8P	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Frovatriptan.	[50]
Naratriptan	DMO50U2	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Naratriptan.	[50]
Rizatriptan	DMDJMA3	Approved	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Rizatriptan.	[50]
Glyceryl trinitrate	DMF72W3	Phase 4	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) affects the response to substance of Glyceryl trinitrate.	[51]
Sildenafil	DM4YDAJ	Phase 3 Trial	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3) increases the response of Sildenafil.	[52]

1 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)/G(S)/G(T) subunit beta-3 (GNB3).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[39]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[40]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone affects the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[41]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[42]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[43]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[44]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[45]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3 (GNB3).	[46]

References

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• [5] Quantitative assessment of the association between GNB3 C825T polymorphism and cancer risk.J BUON. 2014 Oct-Dec;19(4):1092-5.
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• [11] A polymorphism in the G protein beta3-subunit gene is associated with bone metastasis risk in breast cancer patients.Breast Cancer Res Treat. 2008 Oct;111(3):449-52. doi: 10.1007/s10549-007-9808-0. Epub 2007 Nov 4.
• [12] G-protein beta-3 subunit genotype predicts enhanced benefit of fixed-dose isosorbide dinitrate and hydralazine: results of A-HeFT.JACC Heart Fail. 2014 Dec;2(6):551-7. doi: 10.1016/j.jchf.2014.04.016. Epub 2014 Oct 8.
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• [14] Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness. Am J Hum Genet. 2016 May 5;98(5):1011-1019. doi: 10.1016/j.ajhg.2016.03.021. Epub 2016 Apr 7.
• [15] Association of G-protein beta3 subunit gene C825T polymorphism with cardiac and cerebrovascular events in Chinese hypertensive patients.Clin Exp Hypertens. 2017;39(1):80-84. doi: 10.1080/10641963.2016.1210621. Epub 2017 Jan 9.
• [16] G protein 3 subunit polymorphism and long-term prognosis of functional dyspepsia.Gut Liver. 2014 May;8(3):271-6. doi: 10.5009/gnl.2014.8.3.271.
• [17] The G-protein 3 polymorphism is associated with diffuse type gastric cancer in Japanese.Asian Pac J Cancer Prev. 2010;11(5):1195-9.
• [18] Association of the GNB3 825T-allele with better survival in patients with glioblastoma multiforme.J Cancer Res Clin Oncol. 2010 Sep;136(9):1423-9. doi: 10.1007/s00432-010-0797-8. Epub 2010 Feb 10.
• [19] Association study of the G-protein beta3 subunit C825T polymorphism with disease progression an overall survival in patients with head and neck squamous cell carcinoma.Cancer Epidemiol Biomarkers Prev. 2008 Nov;17(11):3203-7. doi: 10.1158/1055-9965.EPI-08-0616.
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• [21] C825T polymorphism in the G protein beta3-subunit gene is associated with seasonal affective disorder.Biol Psychiatry. 2003 Oct 1;54(7):682-6. doi: 10.1016/s0006-3223(03)00169-0.
• [22] The prevalence of Gly972Arg and C825T polymorphisms in Slovak women with polycystic ovary syndrome and their relation to the metabolic syndrome.Gynecol Endocrinol. 2010 May;26(5):356-60. doi: 10.3109/09513590903511497.
• [23] Association between single nucleotide polymorphisms in ADRB2, GNB3 and GSTP1 genes and high-altitude pulmonary edema (HAPE) in the Chinese Han population.Oncotarget. 2017 Mar 14;8(11):18206-18212. doi: 10.18632/oncotarget.15309.
• [24] Recessive Retinopathy Consequent on Mutant G-Protein Subunit 3 (GNB3).JAMA Ophthalmol. 2016 Aug 1;134(8):924-7. doi: 10.1001/jamaophthalmol.2016.1543.
• [25] The CC genotype of the C825T polymorphism of the G protein beta3 gene (GNB3) is associated with a high relapse rate in patients with chronic lymphocytic leukaemia.Leuk Lymphoma. 2003 Oct;44(10):1739-43. doi: 10.1080/1042819031000111017.
• [26] Estimation of the relationship between the polymorphisms of selected genes: ACE, AGTR1, TGF1 and GNB3 with the occurrence of primary vesicoureteral reflux.Int Urol Nephrol. 2017 Mar;49(3):387-397. doi: 10.1007/s11255-016-1483-9. Epub 2016 Dec 17.
• [27] G Protein 3 subunit gene C825T polymorphism and its association with the presence and clinicopathological characteristics of prostate cancer.J Urol. 2012 Jul;188(1):287-93. doi: 10.1016/j.juro.2012.02.2557. Epub 2012 May 16.
• [28] Association between 5-HT2A, TPH1 and GNB3 genotypes and response to typical neuroleptics: a serotonergic approach.BMC Psychiatry. 2007 May 23;7:22. doi: 10.1186/1471-244X-7-22.
• [29] Ablation of the GNB3 gene in mice does not affect body weight, metabolism or blood pressure, but causes bradycardia.Cell Signal. 2014 Nov;26(11):2514-20. doi: 10.1016/j.cellsig.2014.07.030. Epub 2014 Aug 2.
• [30] Association study of the G-protein beta3 subunit C825T polymorphism with disease progression in patients with bladder cancer.World J Urol. 2005 Sep;23(4):279-86. doi: 10.1007/s00345-005-0006-6. Epub 2005 Nov 8.
• [31] G-protein beta(3)-subunit C825T genotype and nephropathy in diabetes mellitus.Nephrol Dial Transplant. 2000 Sep;15(9):1384-7. doi: 10.1093/ndt/15.9.1384.
• [32] Prognostic assessment of three single-nucleotide polymorphisms (GNB3 825C>T, BCL2-938C>A, MCL1-386C>G) in extrahepatic cholangiocarcinoma.Cancer Invest. 2010 Jun;28(5):472-8. doi: 10.3109/07357900903095714.
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• [34] Association of the G-protein 3 subunit gene polymorphism with the incidence of cardiovascular disease independent of hypertension: the Funagata study.J Hum Hypertens. 2013 Oct;27(10):612-6. doi: 10.1038/jhh.2013.28. Epub 2013 Apr 18.
• [35] Detection and interpretation of shared genetic influences on 42 human traits.Nat Genet. 2016 Jul;48(7):709-17. doi: 10.1038/ng.3570. Epub 2016 May 16.
• [36] Lack of an association of GNB3 C825T polymorphism and blood pressure in patients with rheumatoid arthritis.Clin Exp Hypertens. 2009 Jul;31(5):428-39. doi: 10.1080/10641960802668748.
• [37] A splice variant of GNB3 and peripheral polyneuropathy in type 1 diabetes.Dis Markers. 2009;26(3):111-7. doi: 10.3233/DMA-2009-0620.
• [38] 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.
• [39] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [40] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [41] Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake. Obesity (Silver Spring). 2010 Jan;18(1):27-34. doi: 10.1038/oby.2009.208. Epub 2009 Jun 25.
• [42] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [43] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [44] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [45] 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.
• [46] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [47] G-protein gene 825C>T polymorphism is associated with response to clozapine in Brazilian schizophrenics. Pharmacogenomics. 2008 Oct;9(10):1429-36. doi: 10.2217/14622416.9.10.1429.
• [48] Age-dependent antidepressant pharmacogenomics: polymorphisms of the serotonin transporter and G protein beta3 subunit as predictors of response to fluoxetine and nortriptyline. Int J Neuropsychopharmacol. 2003 Dec;6(4):339-46. doi: 10.1017/S1461145703003663.
• [49] Weight loss and body fat reduction under sibutramine therapy in obesity with the C825T polymorphism in the GNB3 gene. Pharmacogenet Genomics. 2009 Sep;19(9):730-3. doi: 10.1097/FPC.0b013e3283307cf1.
• [50] G protein beta3 polymorphism and triptan response in cluster headache. Clin Pharmacol Ther. 2007 Oct;82(4):396-401. doi: 10.1038/sj.clpt.6100159. Epub 2007 Mar 14.
• [51] Venous response to nitroglycerin is enhanced in young, healthy carriers of the 825T allele of the G protein beta3 subunit gene (GNB3). Clin Pharmacol Ther. 2003 Nov;74(5):499-504. doi: 10.1016/S0009-9236(03)00230-3.
• [52] Sildenafil response is influenced by the G protein beta 3 subunit GNB3 C825T polymorphism: a pilot study. J Urol. 2003 Mar;169(3):1048-51. doi: 10.1097/01.ju.0000058369.72348.ba.