Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLE25K3)

• DOT Name: Gonadotropin-releasing hormone receptor (GNRHR)
• Synonyms: GnRH receptor; GnRH-R
• Gene Name: GNRHR
• Related Disease:
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Hypogonadotropic hypogonadism
• UniProt ID: GNRHR_HUMAN
• PDB ID: 7BR3
• Pfam ID: PF00001
• Sequence:
  MANSASPEQNQNHCSAINNSIPLMQGNLPTLTLSGKIRVTVTFFLFLLSATFNASFLLKL
  QKWTQKKEKGKKLSRMKLLLKHLTLANLLETLIVMPLDGMWNITVQWYAGELLCKVLSYL
  KLFSMYAPAFMMVVISLDRSLAITRPLALKSNSKVGQSMVGLAWILSSVFAGPQLYIFRM
  IHLADSSGQTKVFSQCVTHCSFSQWWHQAFYNFFTFSCLFIIPLFIMLICNAKIIFTLTR
  VLHQDPHELQLNQSKNNIPRARLKTLKMTVAFATSFTVCWTPYYVLGIWYWFDPEMLNRL
  SDPVNHFFFLFAFLNPCFDPLIYGYFSL
• Function: Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.
• Tissue Specificity: Pituitary, ovary, testis, breast and prostate but not in liver and spleen.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  GnRH sig.ling pathway (hsa04912)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Hormone ligand-binding receptors (R-HSA-375281)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Strong	Autosomal recessive	[1]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Gonadotropin-releasing hormone receptor (GNRHR) affects the response to substance of Doxorubicin.	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Gonadotropin-releasing hormone receptor (GNRHR).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Gonadotropin-releasing hormone receptor (GNRHR).	[4]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Gonadotropin-releasing hormone receptor (GNRHR).	[5]
1,6-hexamethylene diisocyanate	DMLB3RT	Investigative	1,6-hexamethylene diisocyanate affects the expression of Gonadotropin-releasing hormone receptor (GNRHR).	[6]
Maleic Acid	DM4L0R7	Investigative	Maleic Acid increases the expression of Gonadotropin-releasing hormone receptor (GNRHR).	[7]

References

• [1] Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration. J Clin Endocrinol Metab. 1999 Mar;84(3):990-6. doi: 10.1210/jcem.84.3.5518.
• [2] Mice harboring Gnrhr E90K, a mutation that causes protein misfolding and hypogonadotropic hypogonadism in humans, exhibit testis size reduction and ovulation failure. Mol Endocrinol. 2012 Nov;26(11):1847-56. doi: 10.1210/me.2012-1072. Epub 2012 Aug 23.
• [3] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [4] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [5] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [6] Gene profiles of THP-1 macrophages after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. Toxicol In Vitro. 2009 Sep;23(6):1151-62. doi: 10.1016/j.tiv.2009.06.007. Epub 2009 Jun 13.
• [7] Profiling transcriptomes of human SH-SY5Y neuroblastoma cells exposed to maleic acid. PeerJ. 2017 Apr 5;5:e3175.
• [8] Increase of doxorubicin-induced apoptosis after knock-down of gonadotropin-releasing hormone receptor expression in human endometrial, ovarian and breast cancer cells. Gynecol Endocrinol. 2008 Jan;24(1):24-9. doi: 10.1080/09513590701668882.