Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYOC1RQ)

• DOT Name: Metabotropic glycine receptor (GPR158)
• Synonyms: mGlyR; G-protein coupled receptor 158
• Gene Name: GPR158
• Related Disease:
  Diabetic kidney disease
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Adult glioblastoma
  Astrocytoma
  Depression
  Glioblastoma multiforme
  Glioma
  Lung adenocarcinoma
  Major depressive disorder
  Parkinson disease
  Advanced cancer
  Castration-resistant prostate carcinoma
  Glaucoma/ocular hypertension
  Hepatitis C virus infection
  Neoplasm
  Ocular hypertension
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
• UniProt ID: MGLYR_HUMAN
• PDB ID: 7EWL; 7EWP; 7EWR; 7SHE; 7SHF
• Pfam ID: PF00003
• Sequence:
  MGAMAYPLLLCLLLAQLGLGAVGASRDPQGRPDSPRERTPKGKPHAQQPGRASASDSSAP
  WSRSTDGTILAQKLAEEVPMDVASYLYTGDSHQLKRANCSGRYELAGLPGKWPALASAHP
  SLHRALDTLTHATNFLNVMLQSNKSREQNLQDDLDWYQALVWSLLEGEPSISRAAITFST
  DSLSAPAPQVFLQATREESRILLQDLSSSAPHLANATLETEWFHGLRRKWRPHLHRRGPN
  QGPRGLGHSWRRKDGLGGDKSHFKWSPPYLECENGSYKPGWLVTLSSAIYGLQPNLVPEF
  RGVMKVDINLQKVDIDQCSSDGWFSGTHKCHLNNSECMPIKGLGFVLGAYECICKAGFYH
  PGVLPVNNFRRRGPDQHISGSTKDVSEEAYVCLPCREGCPFCADDSPCFVQEDKYLRLAI
  ISFQALCMLLDFVSMLVVYHFRKAKSIRASGLILLETILFGSLLLYFPVVILYFEPSTFR
  CILLRWARLLGFATVYGTVTLKLHRVLKVFLSRTAQRIPYMTGGRVMRMLAVILLVVFWF
  LIGWTSSVCQNLEKQISLIGQGKTSDHLIFNMCLIDRWDYMTAVAEFLFLLWGVYLCYAV
  RTVPSAFHEPRYMAVAVHNELIISAIFHTIRFVLASRLQSDWMLMLYFAHTHLTVTVTIG
  LLLIPKFSHSSNNPRDDIATEAYEDELDMGRSGSYLNSSINSAWSEHSLDPEDIRDELKK
  LYAQLEIYKRKKMITNNPHLQKKRCSKKGLGRSIMRRITEIPETVSRQCSKEDKEGADHG
  TAKGTALIRKNPPESSGNTGKSKEETLKNRVFSLKKSHSTYDHVRDQTEESSSLPTESQE
  EETTENSTLESLSGKKLTQKLKEDSEAESTESVPLVCKSASAHNLSSEKKTGHPRTSMLQ
  KSLSVIASAKEKTLGLAGKTQTAGVEERTKSQKPLPKDKETNRNHSNSDNTETKDPAPQN
  SNPAEEPRKPQKSGIMKQQRVNPTTANSDLNPGTTQMKDNFDIGEVCPWEVYDLTPGPVP
  SESKVQKHVSIVASEMEKNPTFSLKEKSHHKPKAAEVCQQSNQKRIDKAEVCLWESQGQS
  ILEDEKLLISKTPVLPERAKEENGGQPRAANVCAGQSEELPPKAVASKTENENLNQIGHQ
  EKKTSSSEENVRGSYNSSNNFQQPLTSRAEVCPWEFETPAQPNAGRSVALPASSALSANK
  IAGPRKEEIWDSFKV
• Function: Metabotropic receptor for glycine that controls synapse formation and function in the brain. Acts as an atypical G-protein coupled receptor that recruits and regulates the RGS7-GNB5 complex instead of activating G proteins. In absence of glycine ligand, promotes the GTPase activator activity of RGS7, increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. Glycine-binding changes the conformation of the intracellular surface, inhibiting the GTPase activator activity of the RGS7-GNB5 complex, promoting G protein alpha subunits into their active GTP-bound form and regulating cAMP levels. Also able to bind taurine, a compound closely related to glycine, but with a two-fold lower affinity. Glycine receptor-dependent regulation of cAMP controls key ion channels, kinases and neurotrophic factors involved in neuronal excitability and synaptic transmission. Plays a pivotal role in regulating mood and cognition via its ability to regulate neuronal excitability in L2/L3 pyramidal neurons of the prefrontal cortex. Also involved in spatial learning by regulating hippocampal CA1 neuronal excitability. Acts as a synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure and induces presynaptic differentiation in contacting axons via its interaction with GPC4. In addition to glycine, may also act as a receptor for osteocalcin (BGLAP) hormone: osteocalcin-binding initiates a signaling response that prevents neuronal apoptosis in the hippocampus and regulates the synthesis of neurotransmitters.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic kidney disease	DISJMWEY	Definitive	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Astrocytoma	DISL3V18	Strong	Altered Expression	[3]
Depression	DIS3XJ69	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[5]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[8]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[8]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Altered Expression	[9]
Hepatitis C virus infection	DISQ0M8R	Limited	Genetic Variation	[10]
Neoplasm	DISZKGEW	Limited	Altered Expression	[8]
Ocular hypertension	DISC2BT9	Limited	Biomarker	[11]
Prostate cancer	DISF190Y	Limited	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Metabotropic glycine receptor (GPR158).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metabotropic glycine receptor (GPR158).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Metabotropic glycine receptor (GPR158).	[13]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Metabotropic glycine receptor (GPR158).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Metabotropic glycine receptor (GPR158).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Metabotropic glycine receptor (GPR158).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Metabotropic glycine receptor (GPR158).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Metabotropic glycine receptor (GPR158).	[19]

References

• [1] A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.Diabetes. 2018 Jul;67(7):1414-1427. doi: 10.2337/db17-0914. Epub 2018 Apr 27.
• [2] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [3] Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades.Oncogene. 2018 Aug;37(31):4313-4333. doi: 10.1038/s41388-018-0277-1. Epub 2018 May 3.
• [4] 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.
• [5] Up-regulation of long non-coding RNA SPRY4-IT1 promotes tumor cell migration and invasion in lung adenocarcinoma.Oncotarget. 2017 Apr 7;8(31):51058-51065. doi: 10.18632/oncotarget.16918. eCollection 2017 Aug 1.
• [6] Orphan receptor GPR158 controls stress-induced depression.Elife. 2018 Feb 8;7:e33273. doi: 10.7554/eLife.33273.
• [7] Mapping Spatiotemporal Microproteomics Landscape in Experimental Model of Traumatic Brain Injury Unveils a link to Parkinson's Disease.Mol Cell Proteomics. 2019 Aug;18(8):1669-1682. doi: 10.1074/mcp.RA119.001604. Epub 2019 Jun 16.
• [8] Expression and functional role of orphan receptor GPR158 in prostate cancer growth and progression.PLoS One. 2015 Feb 18;10(2):e0117758. doi: 10.1371/journal.pone.0117758. eCollection 2015.
• [9] Nonclassical Ligand-Independent Regulation of Go Protein by an Orphan Class C G-Protein-Coupled Receptor.Mol Pharmacol. 2019 Aug;96(2):233-246. doi: 10.1124/mol.118.113019. Epub 2019 Jun 12.
• [10] Multi-Ancestry Genome-Wide Association Study of Spontaneous Clearance of Hepatitis C Virus.Gastroenterology. 2019 Apr;156(5):1496-1507.e7. doi: 10.1053/j.gastro.2018.12.014. Epub 2018 Dec 26.
• [11] GPR158, an orphan member of G protein-coupled receptor Family C: glucocorticoid-stimulated expression and novel nuclear role.PLoS One. 2013;8(2):e57843. doi: 10.1371/journal.pone.0057843. Epub 2013 Feb 25.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] 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.
• [17] 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.
• [18] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [19] 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.