Details of Drug Off-Target (DOT)

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

• DOT Name: Succinate receptor 1 (SUCNR1)
• Synonyms: G-protein coupled receptor 91; P2Y purinoceptor 1-like
• Gene Name: SUCNR1
• UniProt ID: SUCR1_HUMAN
• Pfam ID: PF00001
• Sequence:
  MLGIMAWNATCKNWLAAEAALEKYYLSIFYGIEFVVGVLGNTIVVYGYIFSLKNWNSSNI
  YLFNLSVSDLAFLCTLPMLIRSYANGNWIYGDVLCISNRYVLHANLYTSILFLTFISIDR
  YLIIKYPFREHLLQKKEFAILISLAIWVLVTLELLPILPLINPVITDNGTTCNDFASSGD
  PNYNLIYSMCLTLLGFLIPLFVMCFFYYKIALFLKQRNRQVATALPLEKPLNLVIMAVVI
  FSVLFTPYHVMRNVRIASRLGSWKQYQCTQVVINSFYIVTRPLAFLNSVINPVFYFLLGD
  HFRDMLMNQLRHNFKSLTSFSRWAHELLLSFREK
• Function: G protein-coupled receptor for succinate able to mediate signaling through Gq/GNAQ or Gi/GNAI second messengers depending on the cell type and the processes regulated. Succinate-SUCNR1 signaling serves as a link between metabolic stress, inflammation and energy homeostasis. In macrophages, plays a range of immune-regulatory roles. During inflammation, succinate-SUCNR1 signaling may act as an anti-inflammatory mediator or boost inflammation depending on the inflammatory status of cells. Hyperpolarizes M2 macrophages versus M1 phenotype through Gq signaling by regulating the transcription of genes involoved in immune function. In activated M1 macrophages, plays a pro-inflammatory role in response to LPS. Expressed in dendritic cells, where it is involved in the sensing of immunological danger and enhances immunity. Mediates succinate triggered intracelleular calcium mobilization, induces migratory responses and acts in synergy with Toll-like receptor ligands for the production of proinflammatory cytokines as well as an enhancement of antigen-specific activation of helper T cells. In the small intestine, mediates the activation of tuft cells by dietary succinate and triggers type 2 immunity. In adipocytes, plays an important role in the control of energy metabolism. In response to succinate, controls leptin expression in an AMPK-JNK-CEBPA-dependent as well as circadian clock-regulated manner. In muscle tissue, is expressed in non-muscle cells and coordinates muscle remodeling in response to the succinate produced during exercise training in a paracrine manner. In retina, acts as a mediator of vessel growth during retinal development. In response to succinate, regulates the production of angiogenic factors, including VEGF, by retinal ganglion neurons.
• Tissue Specificity: Expressed specifically in kidney . Highly expressed in immature dendritic cells, expression rapidly downregulates after maturation. Also expressed in macrophages .
• KEGG Pathway: cAMP sig.ling pathway (hsa04024)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

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 increases the expression of Succinate receptor 1 (SUCNR1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Succinate receptor 1 (SUCNR1).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Succinate receptor 1 (SUCNR1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Succinate receptor 1 (SUCNR1).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Succinate receptor 1 (SUCNR1).	[5]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Succinate receptor 1 (SUCNR1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Succinate receptor 1 (SUCNR1).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Succinate receptor 1 (SUCNR1).	[1]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Succinate receptor 1 (SUCNR1).	[8]

References

• [1] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] 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.
• [6] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [8] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.