Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT89UWAR)

• DOT Name: Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3)
• Synonyms: G(i) alpha-3
• Gene Name: GNAI3
• Related Disease:
  Auriculocondylar syndrome 1
  Auriculocondylar syndrome
• UniProt ID: GNAI3_HUMAN
• PDB ID: 2IHB; 2ODE; 2V4Z; 4G5O; 4G5R; 4G5S; 7E9H; 7KH0; 7RA3; 7RGP; 7T10; 7T11; 7X6I; 8GVX; 8JD6
• Pfam ID: PF00503
• Sequence:
  MGCTLSAEDKAAVERSKMIDRNLREDGEKAAKEVKLLLLGAGESGKSTIVKQMKIIHEDG
  YSEDECKQYKVVVYSNTIQSIIAIIRAMGRLKIDFGEAARADDARQLFVLAGSAEEGVMT
  PELAGVIKRLWRDGGVQACFSRSREYQLNDSASYYLNDLDRISQSNYIPTQQDVLRTRVK
  TTGIVETHFTFKDLYFKMFDVGGQRSERKKWIHCFEGVTAIIFCVALSDYDLVLAEDEEM
  NRMHESMKLFDSICNNKWFTETSIILFLNKKDLFEEKIKRSPLTICYPEYTGSNTYEEAA
  AYIQCQFEDLNRRKDTKEIYTHFTCATDTKNVQFVFDAVTDVIIKNNLKECGLY
• Function: Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins. Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels. Stimulates the activity of receptor-regulated K(+) channels. The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.
• 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)
  G alpha (s) signalling events (R-HSA-418555)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Auriculocondylar syndrome 1	DIS5C8TJ	Definitive	Autosomal dominant	[1]
Auriculocondylar syndrome	DISW3W1P	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[9]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[11]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[16]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[17]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[17]
biochanin A	DM0HPWY	Investigative	biochanin A decreases the expression of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Guanine nucleotide-binding protein G(i) subunit alpha-3 (GNAI3).	[12]

References

• [1] Transmission of the dysgnathia complex from mother to daughter. Am J Med Genet. 2000 Nov 27;95(3):269-74.
• [2] A human homeotic transformation resulting from mutations in PLCB4 and GNAI3 causes auriculocondylar syndrome. Am J Hum Genet. 2012 May 4;90(5):907-14. doi: 10.1016/j.ajhg.2012.04.002.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] 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.
• [9] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [10] High levels of caveolar cholesterol inhibit progesterone-induced genomic actions in human and guinea pig gallbladder muscle. Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G948-54. doi: 10.1152/ajpgi.90699.2008. Epub 2009 Feb 12.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [14] 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.
• [15] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [18] Mechanisms of the growth inhibitory effects of the isoflavonoid biochanin A on LNCaP cells and xenografts. Prostate. 2002 Aug 1;52(3):201-12.