HGNC Approved Gene Symbol: GPR17Cytogenetic location: 2q14.3 Genomic coordinates (GRCh38): 2:127,646,152-127,652,638 (from NCBI)▼ Cloning and ExpressionMembe...
HGNC Approved Gene Symbol: GPR17
Cytogenetic location: 2q14.3 Genomic coordinates (GRCh38): 2:127,646,152-127,652,638 (from NCBI)
▼ Cloning and Expression
Members of the G protein-coupled receptor (GPCR) superfamily contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. By PCR using degenerate oligonucleotides based on regions conserved between IL8RA (146929) and the angiotensin II chemokine GPCR (106165), Raport et al. (1996) isolated the GPR17 gene, which they called R12. Independently, Blasius et al. (1998) used RT-PCR to identify novel P2 nucleotide (P2Y) GPCRs (see 601167) and isolated GPR17 cDNAs. They identified 2 GPR17 splice variants, designated HIP4 and FB1, which encode predicted proteins of 339 and 367 amino acids, respectively. Northern blot analysis revealed that human GPR17 is expressed as 2.3- and 6.3-kb mRNAs exclusively in brain. The 2 transcripts appear to represent alternatively polyadenylated variants. Based on protein sequence homology and the conservation of certain key residues, GPR17 appears to be closely related to the P2Y family of GPCRs. However, Blasius et al. (1998) stated that preliminary functional data did not support the hypothesis that classical P2Y agonists serve as ligands for this receptor.
▼ Gene Function
Ciana et al. (2006) expressed GPR17 in different cell lines and found that stimulation with both uracil nucleotides and cysteinyl-leukotrienes (CysLTs) resulted in specific and concentration-dependent responses. In vivo, knockdown of Gpr17 by either CysLT receptor (CYSLTR1; 300201) or P2Y receptor (e.g., P2RY12; 600515) antagonists or by antisense technology prevented evolution of brain damage in a rat focal ischemia model. RT-PCR analysis detected expression of GPR17 in human and rat organs prone to ischemic damage, including brain, kidney, and heart. GPR17 appeared to possess 2 distinct binding sites, one for nucleotides and the other for CysLTs. Ciana et al. (2006) concluded that GPR17 is a common molecular target that may mediate ischemia and inflammatory effects induced by nucleotides and CysLTs.
Using mouse cDNAs, Maekawa et al. (2009) showed that Gpr17 downregulated the function, but not the membrane localization, of the cysteinyl leukotriene receptor Cyslt1r (CYSLTR1; 300201). Cotransfection of Gpr17 with Cyslt1r suppressed LTD4 binding and inhibited Cyslt1r-mediated Erk (see MAPK1; 176948) phosphorylation in response to LTD4. Coimmunoprecipitation studies revealed that Gpr17 and Cyslt1r interacted directly. Confocal immunofluorescence microscopy revealed colocalization of GPR17 and CYSLT1R on the surface of human peripheral blood monocytes. Silencing of Gpr17 in mouse bone marrow-derived macrophages increased Cyslt1r membrane expression and increased the magnitude and sensitivity to LTD4-induced calcium flux. Gpr17 deficiency in mice increased Cyslt1r-mediated vascular permeability in IgE-dependent mast cell-mediated passive cutaneous anaphylaxis. The vascular leak in Gpr17-deficient mice was markedly and significantly suppressed by pharmacologic inhibition of Cyslt1r. Maekawa et al. (2009) concluded that GPR17 functions as a negative regulator of CYSLT1R.
Mouse hypothalamic neurons expressing Agrp (602311) are involved in feeding behavior. Ren et al. (2012) found that ablation of Foxo1 (136533) specifically in Agrp-positive hypothalamic neurons resulted in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to leptin and insulin in mice. Quantitative PCR and microarray analysis showed that Gpr17 was highly expressed in Agrp-positive mouse neurons and that Gpr17 expression increased during fasting. Gpr17 expression was decreased in Foxo1-deficient Agrp-positive neurons. Chromatin immunoprecipitation analysis confirmed that Foxo1 bound the Gpr17 promoter. Ren et al. (2012) concluded that downregulation of Gpr17, at least in part, mediates the anorexigenic phenotype of Foxo1-deficient Agrp-positive neurons.
▼ Gene Structure
Blasius et al. (1998) noted that the organization of the GPR17 gene differs from that of many other GPCRs in that the ORF is distributed on 2 exons, with an additional exon containing the 5-prime UTR.
By analysis of somatic cell hybrids, Raport et al. (1996) mapped the R12 gene to chromosome 2. Blasius et al. (1998) regionalized the HIP4/FB1 gene to chromosome 2q21 using fluorescence in situ hybridization.