Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOV08EV)

• DOT Name: G-protein coupled receptor 37-like 1 (GPR37L1)
• Synonyms: Endothelin B receptor-like protein 2; ETBR-LP-2
• Gene Name: GPR37L1
• Related Disease:
  Adult glioblastoma
  Alzheimer disease
  Glioblastoma multiforme
  Glioma
  Medulloblastoma
  Neoplasm
  Parkinson disease
  Progressive myoclonus epilepsy
  High blood pressure
• UniProt ID: G37L1_HUMAN
• Pfam ID: PF00001
• Sequence:
  MRWLWPLAVSLAVILAVGLSRVSGGAPLHLGRHRAETQEQQSRSKRGTEDEEAKGVQQYV
  PEEWAEYPRPIHPAGLQPTKPLVATSPNPGKDGGTPDSGQELRGNLTGAPGQRLQIQNPL
  YPVTESSYSAYAIMLLALVVFAVGIVGNLSVMCIVWHSYYLKSAWNSILASLALWDFLVL
  FFCLPIVIFNEITKQRLLGDVSCRAVPFMEVSSLGVTTFSLCALGIDRFHVATSTLPKVR
  PIERCQSILAKLAVIWVGSMTLAVPELLLWQLAQEPAPTMGTLDSCIMKPSASLPESLYS
  LVMTYQNARMWWYFGCYFCLPILFTVTCQLVTWRVRGPPGRKSECRASKHEQCESQLNST
  VVGLTVVYAFCTLPENVCNIVVAYLSTELTRQTLDLLGLINQFSTFFKGAITPVLLLCIC
  RPLGQAFLDCCCCCCCEECGGASEASAANGSDNKLKTEVSSSIYFHKPRESPPLLPLGTP
  C
• Function: G-protein coupled receptor. Has been shown to bind the neuroprotective and glioprotective factor prosaposin (PSAP), leading to endocytosis followed by an ERK phosphorylation cascade. However, other studies have shown that prosaposin does not increase activity. It has been suggested that GPR37L1 is a constitutively active receptor which signals through the guanine nucleotide-binding protein G(s) subunit alpha. Participates in the regulation of postnatal cerebellar development by modulating the Shh pathway. Regulates baseline blood pressure in females and protects against cardiovascular stress in males. Mediates inhibition of astrocyte glutamate transporters and reduction in neuronal N-methyl-D-aspartate receptor activity.
• Tissue Specificity: Expressed in primary cortical astrocytes (at protein level) . Expressed in the central nervous system .
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Posttranslational Modification	[2]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Progressive myoclonus epilepsy	DISAMCNS	Strong	Genetic Variation	[4]
High blood pressure	DISY2OHH	moderate	Biomarker	[5]

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 G-protein coupled receptor 37-like 1 (GPR37L1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of G-protein coupled receptor 37-like 1 (GPR37L1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of G-protein coupled receptor 37-like 1 (GPR37L1).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of G-protein coupled receptor 37-like 1 (GPR37L1).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of G-protein coupled receptor 37-like 1 (GPR37L1).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of G-protein coupled receptor 37-like 1 (GPR37L1).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of G-protein coupled receptor 37-like 1 (GPR37L1).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of G-protein coupled receptor 37-like 1 (GPR37L1).	[12]

References

• [1] Genetic ablation of Gpr37l1 delays tumor occurrence in Ptch1(+/-) mouse models of medulloblastoma.Exp Neurol. 2019 Feb;312:33-42. doi: 10.1016/j.expneurol.2018.11.004. Epub 2018 Nov 16.
• [2] Promoter DNA hypermethylation - Implications for Alzheimer's disease.Neurosci Lett. 2019 Oct 15;711:134403. doi: 10.1016/j.neulet.2019.134403. Epub 2019 Jul 24.
• [3] GPR37 and GPR37L1 differently interact with dopamine 2 receptors in live cells.Neuropharmacology. 2019 Jul 1;152:51-57. doi: 10.1016/j.neuropharm.2018.11.009. Epub 2018 Nov 10.
• [4] GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant.Neurobiol Dis. 2017 Oct;106:181-190. doi: 10.1016/j.nbd.2017.07.006. Epub 2017 Jul 6.
• [5] Orphan receptor GPR37L1 contributes to the sexual dimorphism of central cardiovascular control.Biol Sex Differ. 2018 Apr 6;9(1):14. doi: 10.1186/s13293-018-0173-y.
• [6] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] 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.
• [11] 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.
• [12] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.