Copyright © 2013 IUPHAR
Annotated and awaiting review. Please contact us if you can help with reviewing.
GPR15
Family: Class A Orphans
| Gene and Protein Information |
||||||
| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 360 | 3q11.2-q13.1 | GPR15 | G protein-coupled receptor 15 | 17 |
| Mouse | 7 | 360 | 16 C1.2 | Gpr15 | G protein-coupled receptor 15 | |
| Rat | 7 | 377 | 11q12 | Gpr15 | G protein-coupled receptor 15 | |
| Previous and Unofficial Names |
| BOB |
| GPR15 |
| G protein-coupled receptor 15 |
| Brother of Bonzo |
| G-protein coupled receptor 15 |
| Gpr15_predicted |
| LOC288181 |
| G protein-coupled receptor 15 (predicted) |
| 4933439K08Rik |
| BoB |
| Database Links |
|
| Ensembl | ENSG00000154165 (Hs), ENSMUSG00000047293 (Mm), ENSRNOG00000039680 (Rn) |
| Entrez Gene | 2838 (Hs), 71223 (Mm), 288181 (Rn) |
| GeneCards | GPR15 (Hs) |
| GenitoUrinary Development Molecular Anatomy Project | Gpr15 (Mm) |
| HomoloGene | 3869 (Hs) |
| Human Protein Reference Database | 03102 (Hs) |
| InterPro | P49685 (Hs), Q0VDU3 (Mm) |
| KEGG Gene | hsa:2838 (Hs), mmu:71223 (Mm), rno:288181 (Rn) |
| OMIM | 601166 (Hs) |
| PharmGKB Gene | PA28858 (Hs) |
| PhosphoSitePlus | P49685 (Hs), Q0VDU3 (Mm) |
| Protein Ontology (PRO) | PRO:000001418 (Hs) |
| RefSeq Nucleotide | NM_005290 (Hs), NM_001162955 (Mm), NM_001105890 (Rn) |
| RefSeq Protein | NP_005281 (Hs), NP_001156427 (Mm), NP_001099360 (Rn) |
| TreeFam | ENSG00000154165 (Hs), ENSMUSG00000047293 (Mm), ENSRNOG00000039680 (Rn) |
| UniGene Hs. | 563128 (Hs) |
| UniProt | P49685 (Hs), Q0VDU3 (Mm) |
| Wikipedia | GPR15 |
|
Orphan and other 7TM receptors |
| Tissue Distribution
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
||||||||
| Tissue Distribution Comments | ||||||||
| RT-PCR detected GPR15 in phytohaemagglutinin-stimulated in peripheral blood mononuclear cells (PBMC), purified T cells, with weak detection in unstimulated PBMC [11]. The detection of GPR15 in the colon suggestes it may be important for transmission of HIV and SIV, and the authors speculate that the high expression in the colon suggests it may be expressed in non-lymphoid cells [11]. Brain capillary endothelial cells, the targets of CD4 independent infection by HIV-1 and SIV strains were found not to express GPR15 [13]. RT-PCR analysis of CEMX174, Hut-78, C8166, monocytes, monocyte-derived macrophages, and peripheral blood leukocyte cell lines detected GPR15 expression [12]. Not detected in core bone cells by RT-PCR analysis [38]. Human fetal and simian adult astrocytes were shown to express GPR15 when analysed using RT-PCR, and this expression increased following treatment with TNFα and IL-1β [10]. For expression levels on immune cells of primate species see [14]. Analysis of the expression of GPR15 in the rhesus macaque gut showed that gut epithelial cell apoptosis coincided with interactions between SIV virus and GPR15-expressing cells [24]. |
||||||||
| Expression Datasets |
|
|
| Gene Expression and Pathophysiology Comments | |
| GPR15 mediates the gp120-induced calcium signaling and microtubule loss in HIV-infected cells. The authors speculate that activation of GPR15 induced by gpr120 is a probable cause of HIV enteropathy [8]. It has been shown that the effects of gpr120-mediated enteropathy of the intestine, including microtubule depolymerisation, can be inhibited by anitbodies against GPR15 through disruption of signal transduction [26]. |
| Biologically Significant Variants
|
||||||||||
|
||||||||||
|
||||||||||
|
||||||||||
| Biologically Significant Variant Comments | ||||||||||
| There was no correlation observed between polymorphisms in the GPR15 gene in humans with plasma viral concentration [46]. | ||||||||||
| General Comments |
|
The mouse orthologue of gpr15 can be induced by dioxin, confirmed by reverse northern analysis [37]. It has been reported by several studies that GPR15 acts as a co-receptor for HIV, and is used by HIV-2 strains [9,13,16,19,29,42]. There is some disagreement in the literature as to whether GPR15 is also used as a coreceptor by HIV-1 strains, with some studies finding it is not [49], while others showing it is used by some strains but the significance of its use in relation to other coreceptors is unclear [4]. R5X4 HIV-1 strains have been shown to use GPR15 as a coreceptor [6-7]. Chan et al. discuss the difficulty in studying the role of GPR15 as a coreceptor. Later studies showed that some HIV-1 strains do use GPR15 as a coreceptor and replicate within GPR15-expressing cells, albeit with lower efficiency than other receptors [30,34]. Use of GPR15 as a coreceptor depends on the genetic subtype and biological phenotype of the strain, and in its role as a cofactor GPR15 may be important in influencing the pathogenesis and transmission of HIV [34]. GPR15 is also a co-receptor for primary SIV strains [11,15,49]. This has been demonstrated using GHOST and U87 cell line assays [32]. It has also been shown that the use of GPR15 for cell entry by SIV strains is comparable in its efficiency with use of CCR5, and that SIVmac strains of the virus from rhesus macaques can use both the human and simian receptors [35]. However a later study showed that GPR15 was used with less efficiency than CCR5 by SIV strains and is rarely used by HIV-1 strains [43]. A high degree of sequence similarity has been shown between the human and Rhesus macaque receptors [27]. Edinger et al. showed that GPR15 is used in the entry mechanism of a number of SIV strains but use of the receptor did not correlate with either SIV or HIV tropism [12]. SIV strains SIVmac251 and SIVmac239 has been shown to utilise GPR15 as a coreceptor [23,49], and other SIVmac strains show preferential use of GPR15 over other coreceptors [36,42]. A macrophage-tropic SIVMne clone was shown to use GPR15 as a coreceptor [21]. Envelope proteins from HIV and SIV strains have been found to utilise GPR15 to enable their entry into cells [18,41], and that cell entry via fusion with GPR15 is CD4-dependent [1,12-13]. However, a more recent study has shown GPR15 to have a role in CD4-independent cell entry [39]. Eight HIV-1 envelope glycoproteins can use GPR15 to enable cell entry [30]. SIV/17E-Fr, SIV/B670-Cl 3, and SIVsmE543 envelope proteins may mediate fusion with cells expressing CD4 and GPR15 [13]. It is speculated that variation in the expression pattern of GPR15 may be a contributing factor in determining the outcome of SIV infection [12]. Xiao et al. shows the correlation between the adaptation of viral strains to use co-receptors and infectivity/disease progression, implying that as a coreceptor there may be future interest in GPR15 as a therapeutic target [47]. Entry via GPR15 of a SIVmac239 clone is shown to be dependent on a single amino acid residue in the V3 loop of the clone [36]. However, this study also states that the role of GPR15 in the pathogenesis and replication of HIV-2 and SIV strains is unclear. Inhibition of the SIV envelope protein-mediated fusion with GPR15-expressing cells are explored by [48] and by the use of amino acid substitutions in the SIV Env protein by Meister et al [2]. Their results shows that GPR15-utilisation can be imparied by a L320K-P321R substution in the N-terminal half of the SIVmac V3 loop. Other substitutions in the V3 loop of SIV envelope protein have been shown to disrupt use of GPR15 as a coreceptor [19,33]. The importance of the V3 loop is confirmed by [19]. There is a high degree of sequence similarity between human and monkey receptors GPR15 receptors [11] and a high degree of sequence similarity between the amino-terminal regions of GPR15 and CCR5. HIV-1 virus strains ADA and YU2 show weak use of GPR15 as a coreceptor [15]. The original cloning study for GPR15 showed sequence similarity with angiotensin receptors AT1 and AT2, the interleukin 8b receptor and the orphan receptors GPR1 and AGTL1 [17]. The high degree of sequence similarity with GPR1 is consistent with the finding that almost all viral strains using GPR15 as a coreceptor also use GPR1 [12]. GPR15 was later shown to have high sequence similarity to GPR25 [20]. Changes in DNA methylation of the the GPR15 gene locus have been linked to cigarette smoking, in an analysis of DNA from peripheral blood leukocytes using Illumina Human methylation 27K Beadchip; these results were validated by pyrosequencing [45]. The results from this study showed hypomethylation of the cg19859270 locus for current smokers and hypermethylation in former smokers when compared to controls. It has been demonstrated that morphine does not affect gene expression of GPR15 [28]. African green monkey strains of SIV have been shown to use GPR15 as a coreceptor but with lower efficiency than CXCR4 [22]. Use of coreceptors by both HIV and SIV strains can evolve over the course of an infection with SIVsm strains showing a decrease in GPR15 use over time [44]. Study of the use of GPR15 as a coreceptor by HIV-2 strains shows that it is one of three coreceptors used mainly by low-pathogenic strains but was also shown to be one of the main coreceptors used in individuals with viremia, indicating there is no correlation between disease progression and coreceptor use [3]. HIV-2 isolates able to fuse with GPR15 in the absence of CD4 include VCP and ROD/B [25]. Cell surface expression of GPR15 is significantly increased following activation of phosphoinositide 3-kinase [5], and is mediated by mode III binding of 14-3-3 proteins to the receptor's C terminus [31]. Xenotropic Murine leukaemia Virus-related virus (XMRV) replication has been observed in cells expressing GPR15 [40]. |
| Available Assays | |||
|
PathHunter® CHO-K1 GPR15 (Orphan) High Expression β-Arrestin Cell Line | Human | Cat No. 93-0682C2 |
|
|
PathHunter® eXpress GPR15 CHO-K1 β-Arrestin (Orphan) GPCR Assay | Human | Cat No. 93-0682E2CP1 |
To cite this database page, please use the following:
Helen E. Benson.
Class A Orphans: GPR15. Last modified on 02/11/2012. Accessed on 20/06/2013. IUPHAR database (IUPHAR-DB), http://iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=87.
Contact us | Print | Back to top | Help