Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP2QEML)

• DOT Name: G-protein coupled receptor 3 (GPR3)
• Synonyms: ACCA orphan receptor
• Gene Name: GPR3
• UniProt ID: GPR3_HUMAN
• Pfam ID: PF00001
• Sequence:
  MMWGAGSPLAWLSAGSGNVNVSSVGPAEGPTGPAAPLPSPKAWDVVLCISGTLVSCENAL
  VVAIIVGTPAFRAPMFLLVGSLAVADLLAGLGLVLHFAAVFCIGSAEMSLVLVGVLAMAF
  TASIGSLLAITVDRYLSLYNALTYYSETTVTRTYVMLALVWGGALGLGLLPVLAWNCLDG
  LTTCGVVYPLSKNHLVVLAIAFFMVFGIMLQLYAQICRIVCRHAQQIALQRHLLPASHYV
  ATRKGIATLAVVLGAFAACWLPFTVYCLLGDAHSPPLYTYLTLLPATYNSMINPIIYAFR
  NQDVQKVLWAVCCCCSSSKIPFRSRSPSDV
• Function: Constitutively active G-protein coupled receptor that maintains high 3'-5'-cyclic adenosine monophosphate (cAMP) levels that a plays a role in serveral processes including meiotic arrest in oocytes or neuronal development via activation of numerous intracellular signaling pathways. Acts as an essential activator of thermogenic adipocytes and drives thermogenesis via its intrinsic G(s)-coupling activity without the requirement of a ligand. Has a potential role in modulating a number of brain functions, including behavioral responses to stress, amyloid-beta peptide generation in neurons. Stimulates neurite outgrowth in cerebellar granular neurons modulated via PKA, ERK, and most strongly PI3K-mediated signaling pathways.
• Tissue Specificity: Expressed predominantly in the central nervous system, and at low levels in the lung, kidney, testis, ovary and eye. Highly expressed in regions of the brain implicated in the Alzheimer disease.

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of G-protein coupled receptor 3 (GPR3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of G-protein coupled receptor 3 (GPR3).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of G-protein coupled receptor 3 (GPR3).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of G-protein coupled receptor 3 (GPR3).	[4]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of G-protein coupled receptor 3 (GPR3).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of G-protein coupled receptor 3 (GPR3).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of G-protein coupled receptor 3 (GPR3).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of G-protein coupled receptor 3 (GPR3).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of G-protein coupled receptor 3 (GPR3).	[10]

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 G-protein coupled receptor 3 (GPR3).	[6]

References

• [1] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [5] Expression of endogenous retroviruses reflects increased usage of atypical enhancers in T cells. EMBO J. 2019 Jun 17;38(12):e101107. doi: 10.15252/embj.2018101107. Epub 2019 May 8.
• [6] 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.
• [7] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [8] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] 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.