Details of Drug Off-Target (DOT)

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

• DOT Name: Gastrin-releasing peptide receptor (GRPR)
• Synonyms: GRP-R; GRP-preferring bombesin receptor
• Gene Name: GRPR
• UniProt ID: GRPR_HUMAN
• PDB ID: 7W3Z; 7W40; 7W41; 8H0Q
• Pfam ID: PF00001
• Sequence:
  MALNDCFLLNLEVDHFMHCNISSHSADLPVNDDWSHPGILYVIPAVYGVIILIGLIGNIT
  LIKIFCTVKSMRNVPNLFISSLALGDLLLLITCAPVDASRYLADRWLFGRIGCKLIPFIQ
  LTSVGVSVFTLTALSADRYKAIVRPMDIQASHALMKICLKAAFIWIISMLLAIPEAVFSD
  LHPFHEESTNQTFISCAPYPHSNELHPKIHSMASFLVFYVIPLSIISVYYYFIAKNLIQS
  AYNLPVEGNIHVKKQIESRKRLAKTVLVFVGLFAFCWLPNHVIYLYRSYHYSEVDTSMLH
  FVTSICARLLAFTNSCVNPFALYLLSKSFRKQFNTQLLCCQPGLIIRSHSTGRSTTCMTS
  LKSTNPSVATFSLINGNICHERYV
• Function: Receptor for gastrin-releasing peptide (GRP). Signals via association with G proteins that activate a phosphatidylinositol-calcium second messenger system, resulting in Akt phosphorylation. Contributes to the regulation of food intake. Contributes to the perception of prurient stimuli and transmission of itch signals in the spinal cord that promote scratching behavior, but does not play a role in the perception of pain. Contributes primarily to nonhistaminergic itch sensation. In one study, shown to act in the amygdala as part of an inhibitory network which inhibits memory specifically related to learned fear. In another study, shown to contribute to disinhibition of glutamatergic cells in the auditory cortex via signaling on vasoactive intestinal peptide-expressing cells which leads to enhanced auditory fear memories. Contributes to the induction of sighing through signaling in the pre-Botzinger complex, a cluster of several thousand neurons in the ventrolateral medulla responsible for inspiration during respiratory activity.
• Tissue Specificity: Highly expressed in pancreas . Also expressed in stomach, adrenal cortex and brain . In brain, expressed in cells throughout the cortex .
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

5 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 Gastrin-releasing peptide receptor (GRPR).	[1]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Gastrin-releasing peptide receptor (GRPR).	[2]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Gastrin-releasing peptide receptor (GRPR).	[3]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gastrin-releasing peptide receptor (GRPR).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Gastrin-releasing peptide receptor (GRPR).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Gastrin-releasing peptide receptor (GRPR).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Gastrin-releasing peptide receptor (GRPR).	[5]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [3] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [4] Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice. Cell Rep. 2018 Apr 17;23(3):866-877. doi: 10.1016/j.celrep.2018.03.087.
• [5] 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.
• [6] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [7] 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.