object_id,name,abbreviation,comments,gtip_comment
1,5-HT1A receptor,,"",The chemoattractant properties of 5-HT on both human and mouse mast cells are mediated by 5-HT1A receptor . Mouse 5-HT1A receptor activation stimulates production of pro-inflammatory cytokines (e.g. IL-1 and IL-6) from peritoneal macrophages in a NF-κB-dependent manner and enhances their phagocytic capacity .
2,5-HT1B receptor,,,The expression of 5-HT1B receptors on immune cells indicates that it plays some part in immune/inflammatory responses .
4,5-ht1e receptor,,,The expression of 5-HT1e receptors on immune cells indicates that it plays some part in immune/inflammatory responses .
6,5-HT2A receptor,,,The chemoattractant properties of 5-HT on human eosinophils is mediated by 5-HT2A receptor .
7,5-HT2B receptor,,,The expression of 5-HT2B receptors on immune cells indicates that it plays some part in immune/inflammatory responses .
8,5-HT2C receptor,,A non-functional short (248aa) splice-variant of the h 5-HT2C receptor has been described .,The expression of 5-HT2B receptors on immune cells indicates that it plays some part in immune/inflammatory responses .
9,5-HT4 receptor,,"",5-HT has been shown to alter cytokine production by dendritic cells via 5-HT4 and 5-HT7 receptors .
12,5-HT7 receptor,,,"5-HT has been shown to alter cytokine production by dendritic cells via 5-HT4 and 5-HT7 receptors . 5-HT7 receptor plays a vital role in 5-HT-stimulated generation of a more inflammatory adaptive immune response, particulary in relation to gut inflammation ."
18,A1 receptor,,For a review of the effects of adenosine receptor knockout on nervous system function see reference .,Adenosine exerts anti-inflammatory effects on a number of immune cells types. These effects are mediated by the adenosine G portein-coupled receptors. All four adenosine receptors are expressed on the surface of mouse invariant NKT (iNKT) cells. The specific role of the A1 receptor in adenosine-mediated anti-inflammatory effects is not fully understood.
19,A2A receptor,,A2A antagonists can be useful as therapy for Parkinson's disease (see reviews ). Istradefylline (see for a review) is marketed in Japan and the USA for this indication.,"Agonist stimulation of the A2A and A3 receptors down-regulates production of the pro-inflammatory mediators TNF-α and IL-8 in human synoviocytes , suggesting a role in controlling arthritic joint inflammation. Experimental evidence indicates that A2A receptor-mediated mechanisms regulate the cytokine secretion pattern of iNKT cells . Arizmendi and Kulka (2018) have demonstrated that adenosine, acting via the A2A receptor, inhibits C3a-mediated activation of human mast cells through a Gαs-dependent pathway, leading the authors to conclude that this pathway may be an important regulator of mast cell activation that is a tractable target for pharmacological intervention in mast cell-mediated allergic inflammation .
The A2A and A2B receptors on immune cells (e.g. T cells, NK cells, dendritic cells and macrophages) mediate the immunosuppressive effects of adenosine, an action that produces a powerful tolerogenic/immunosuppressed state in the tumour microenvironment. As a result, the A2A receptor has been suggested as an immune checkpoint that produces a negative feedback loop in the tumour microenvironment, that is hypothesised to be susceptible to A2A antagonist circumvention as a novel immuno-oncology approach . This could potentially repurpose A2A receptor antagonists that have failed late stage clinical trials (Phase 3) as Parkinson's disease (PD) modulators, such as istradefylline (approved in Japan, but failed to gain US FDA approval for PD), preladenant, ST-1535 and tozadenant, amongst others. A2A receptor is discussed in this immuno-oncology review . The potential therapeutic combination of A2A receptor antagonists with other checkpoint inhibitors in oncology is reveiwed by Garber (2017) , and Table 1 therein highlights some of the A2A antagonist/checkpoint inhibitor combinations that have synergistic anti-cancer potential.
Examples of A2A antagonists in early stage clinical trials in advanced malignancies: AstraZeneca's AZD4635 () in combination with anti-PD-L1 (NCT02740985), Merck's in combination with anti-PD-L1 (NCT03099161), Palobiofarma's () in combination with anti-PD-1 investigational mAb (PDR001, NCT02403193), and Corvus Pharma/Genentech's (CPI-444) in combination with anti-PD-L1 (NCT02655822). Arcus Biosciences' AB928 (structure not disclosed) is a dual A2A/2B antagonist that is in early stage immuno-oncology development . AB928 activity is suggested to be peripherally restricted and is devoid of the CNS-mediated pharmacology of other adenosine receptor antagonists."
20,A2B receptor,,For a review of the effects of adenosine receptor knockout on nervous system function see reference .,A2B receptor is discussed in this immuno-oncology review .
21,A3 receptor,,For a review of the effects of adenosine receptor knockout on nervous system function see reference .,"Agonist stimulation of the A2A and A3 receptors down-regulates production of the pro-inflammatory mediators TNF-α and IL-8 in human synoviocytes , suggesting a role in controlling arthritic joint inflammation.
This protein contains an immunoglobulin (Ig)-like domain that resembles the antibody variable domain, that has been coined the 'V-set domain'. The genes for all human V-set domain containing proteins are listed in HGNC gene group 590."
28,β1-adrenoceptor,,For a review on the β-adrenoceptor polymorphisms see reference .,"β1-AR is involved in immune regulation and inflammation.
Inflammation: Astrocytes and microglia .
Anti-β1-AR autoantibodies: effect on β1-AR conformation and function , in heart failure , cardiac fibrosis , and cardiomyopathy , "
29,β2-adrenoceptor,,For a review on the β-adrenoceptor polymorphisms see reference .,"β2-ARs are expressed on innate and adaptive immune cells of humans and rodents, and are reported to have an immuno-modulating effect .
There is a large literature on the role of autoantibodies to β2-AR associated with a variety of disease processes ."
31,C3a receptor,,,"Complement C3a receptor 1 is the receptor for complement factor C3a, a component of the alternative complement cascade. It can have pro-inflammatory actions, but can also counteract the proinflammatory effects of C5a.
The complement system plays a critical role intestinal immune homeostasis. In particular, C3 and the C3aR have been identified as being involved in regulating the intestinal immune response during chronic colitis . C3aR is also reported to provide protection from tissue damage in an intestinal ischemia-reperfusion model, an effect that is mediated by inhibition of neutrophil mobilisation .
The biological action of C3aR agonists and antagonists can be monitored by measuring receptor-mediated cytokine release from human macrophages , and C3aR biology further examined by assessing granulocyte/neutrophil mobilisation in response to injury or G-CSF ."
32,C5a1 receptor,,"Although C5aR is typically associated with the innate immune system, recently research on the receptor has elucidated novel roles. C5aR has been demonstrated on adult neural progenitor cells , mesenchymal stem cells and perhaps has roles regulating the cell cycle in types of cancer .
Pharmacological inhibition of C5aR signalling ameliorates disease pathology in a mouse model of amyotrophic lateral sclerosis .",C5aR is typically associated with the compement cascade and innate immunity.
MorphoSys have an anti-C5aR monoclonal antibody (MOR210; TJ210) in preclinical development as an immuno-oncology agent. The goal of anti-C5aR therapy is to reduce the effects that activation of the C5a/C5aR axis has on promoting cancer cell migration and invasiveness .
33,C5a2 receptor,,"Binds C5a complement factor, but appears to lack G protein signalling and has been termed a decoy receptor . There remains controversy regarding the ligands (especially C3a des Arg), function (C3a des Arg-mediated control of triglyceride synthesis) and whether it is pro- or anti-inflammatory. ","C5aR is typically associated with the compement cascade and innate immunity. However, the complement C5a receptor 2 may act as a decoy receptor for C5a, as it has no reported G protein signalling capacity."
34,AT1 receptor,,"For information on miRNAs predicted to target AGTR1 3'-UTR please see TargetScan .
Crystallography has confirmed the different conformations that AT1R adopts in Gq-biased and β-arrestin-biased ligand-bound states .
AT1R cross talk with TRPV4 has been observed. Internalization of both the receptors is inhibited by antagonists that independently target either partner in the interaction pair .",Accumulating evidence suggests that regulation of the mutually antagonistic angiotensin receptors AT1 and AT2 is essential for maintaining control of inflammation and that an imbalance between these two receptors has pathophysiological potential .
35,AT2 receptor,,"The ATGR2 appears to be re-expressed or up-regulated after vascular injury, myocardial infarction, cardiac failure or wound healing, possibly reflecting re-activation of a foetal genetic programme
Preclinical in vitro and in vivo studies indicated that the AT2 receptor counterbalances the effect of the AT1 receptor .
The most relevant transcription factor binding sites in the AGTR2 gene promoter:
Most relevant TFs: AP-1, ATF-2, IRF-1, CREB, PPAR-γ1, δCREB, PPAR-γ2, c-Jun.
MiRNAs Predicted to Target AGTR2 3’-UTR:
Predicted miRNAs. Both conserved and poorly conserved sites are shown .","AT2 receptors have been have been identified on human immunocompetent cells, and selective AT2 receptor activation stimulates an anti-inflammatory effect (reduces production of pro-inflammatory cytokines TNFα, IL-6, and IL-10 after LPS challenge) in human monocytes . Experimental work indicates that AT1 and AT2 receptors can modulate the inflammatory NFκB pathway , and AT2 receptors play a role in the recruitment of inflammatory cells. Accumulating evidence suggests that regulation of the mutually antagonistic angiotensin receptors AT1 and AT2 is an essential process in the control of inflammation and that an imbalance between these two receptors has pathophysiological potential . Existing anti-hypertensive drugs could be used to investigate the effect of manipulating the angiotensin system on a variety of diseases."
36,apelin receptor,,The biology of the apelin receptor system has recently been comprehensively reviewed in the works of Kleinz et al. (2005) and Masri et al. (2005) .,"The apelin receptor gene (APLNR) has been identified as one of a number of genes necessary to confer suceptibility of cancer cells to immunotherapy (i.e. T cell recognition and cytolysis) . This effect is likely mediated by apelin receptor/JAK1 upregulation of the IFN-γ response that appears to promote antigen processing and presentation by tumours, and which improves the ability of T cells to recognize and attack the cancer cells. Defects in IFN-γ signalling is a recognised mechanism underlying resistance to immunotherapy . The authors of show that functional loss of APLNR in mouse models reduces the efficacy of immunotherapies (both adoptive cell transfer and checkpoint blockade) and is indicative of poor prognosis."
37,GPBA receptor,,For an overview of bile acids and their role in energy homeostasis see reference .,"The GPBA receptor (GPBAR) was historically identified as a metabolic regulator with roles in energy homeostasis, bile acid homeostasis, and glucose metabolism. More recently additional functions for the GPBA receptor such as regulation of the inflammatory response, cancer and liver regeneration have been described . GPBAR agonists reduce the production of proinflammatory cytokines and stabilize the alternative macrophage phenotype . This action appears to be mediated by regulation of the NLRP3 inflammasome pathway. The GPBAR agonist (INT-777) produces a protective (anti-inflammatory) effect in many inflammatory diseases in vivo , and has recently been shown to attenuate the severity of acute pancreatitis in a mouse model (an effect associated with reduced reactive oxygen species (ROS) production and a reduction in the activation of the NLRP3 inflammasome) ."
41,B1 receptor,,"B1 and B2 receptors are overexpressed in the hippocampus of humans with temporal lobe epilepsy . B1 receptor is overexpressed in the retina of humans affected with the wet form of age-related macular degeneration , and in the retina of diabetic patients .","Bradykinin is a vasoactive, pain inducing and pro-inflammatory kinin released during acute inflammation, and its receptors, B1 and B2, are expressed on eosinophils, and neutrophils."
42,B2 receptor,,B1 and B2 receptors are overexpressed in the hippocampus of humans with temporal lobe epilepsy . ,"Bradykinin is a vasoactive, pain inducing and pro-inflammatory (phlogistic) kinin released during acute inflammation, and its receptors, B1 and B2, are expressed on eosinophils, and neutrophils. The B2 receptor antagonist icatibant was evaluated in a Phase 2 trial for osteoarthritis , but development has not progressed further."
56,CB1 receptor,,Techniques used include in situ hybridization and immunohistochemistry .,"CB1 receptor is involved in controlling mast cell degranulation and maturation , and mediates production of MCP-1 by mast cells which results in recruitment of monocytic myeloid-derived suppressor cells with immunosuppressive outcome . High levels of CB1 expression in the CNS suggest a possible role in neuroinflammation and potential as a drug target ."
57,CB2 receptor,,"Techniques used include Northern blot, in situ hybridization and receptor autoradiography","CB2 receptor on eosinophils mainly mediates anti-inflammatory and immunomodulatory actions e.g. downregulation of pro-inflammatory mediator release. Pharmacological targeting with the CB2 receptor selective antagonist SR144528 attenuates the recruitment of eosinophils and ear swelling in a murine chronic contact dermatitis model ."
58,CCR1,,,CCR1 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
59,CCR2,,,CCR2 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CCR2 is discussed in relation to immuno-oncology in .
60,CCR3,,,CCR3 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
61,CCR4,,,"CCR4 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
In disease states CCR4 is involved in recruiting T helper type 2 cell (Th2) subsets in autoimmune disorders such as asthma, allergic rhinitis, and atopic dermatitis , and recruiting highly immunosuppressive CD4+/CD25+/FOXP3+ regulatory T cells (Treg) cells to the tumour microenvironment . As such antagonists of CCR4 are under investigation for clinical utility in inflammatory diseases and cancer. Of note is the approval of , an anti-CCR4 monoclonal immuno-oncology agent, although its use can produce damaging side effects via depletion of Treg cells and their vital immune functions outwith the targeted tissues. Small molecule CCR4 antagonists have also been developed e.g. and , and which was advanced to Phase 1 clinical trial for asthma but not progressed further ."
62,CCR5,,,"CCR5 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CCR5 is discussed in relation to immuno-oncology in . CCR5 is the only chemokine receptor demonstrated to play an essential role in HIV/AIDS pathogenesis. CCR5 is a co-receptor used by some strains of HIV (the so-called CCR5-tropic strains) to enter host T cells. CytoDyn have an anti-CCR5 monoclonal antibody named leronlimab (PRO140) in clinical development . In the HIV setting PRO140 is classified as a viral-entry inhibitor and is intended to protect healthy cells from viral infection, whilst sparing CCR5's normal function in immune responses. "
63,CCR6,,,"CCR6 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. CCR6 is expressed on a variety of immune cells including memory and regulatory T-cells , naïve and activated B cells , dendritic cells and Th17 T-cells . CCR6 is the main chemokine receptor of Th17 cells, which are implicated in many chronic inflammatory conditions. In addition, CCR6 and its only known ligand , are up-regulated in tissues of patients with chronic inflammatory conditions (e.g. psoriasis, arthritic conditions and inflammatory bowel disease) ."
64,CCR7,,,CCR7 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
65,CCR8,,,CCR8 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
66,CCR9,,,CCR9 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. Activation of CCR9 by CCL25 plays a key role in leukocyte recruitment to the gut and CCR9 antagonists are being pursued as therapeutic agents for inflammatory bowel disease .
67,CCR10,,,CCR10 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
68,CXCR1,,"",CXCR1 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CXCR1 is discussed in relation to immuno-oncology in . It has been shown that CXCR1 receptor expression on epithelial cells is enhanced by bacterial infection (E.coli and H. pylori). This induces transepithelial neutrophil migration and clearing of the infection.
69,CXCR2,,,"CXCR2 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CXCR2 is discussed in relation to immuno-oncology in . From a therapeutic perspective, small molecule CXCR2 antagonists (e.g., AZD5069, danirixin) have been developed to selectively block neutrophilic inflammatory pathways in chronic inflammatory lung diseases. In addition to blocking excessive neutrophil recruitment in blood and to the lungs of more severe asthma patients , AZD5069 can also act as a NET-stabilizing agent to disrupt NET formation in sputum neutrophils derived from patients with COPD ."
70,CXCR3,,,"CXCR3 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CXCR3 is the receptor for CXCL9, -10 and -11, three CXC chemokines that are preferentially expressed on Th1 lymphocytes.
In the cancer setting cytokines are known to establish an immunosuppressive milieu that is condusive to tumour progression. CXCR3 and its ligands have specifically been identified as being associated with this mechanism in pancreatic ductal adenocarcinoma ."
71,CXCR4,,"CXCR4 is a receptor for stromal cell-derived factor-1 (SDF1; CXCL12) . When co-expressed alongside CD4, CXCR4 is involved in HIV-1 infection. It is the major T cell-tropic coreceptor for HIV-1. In contrast, CCR5 serves as the principal macrophage-tropic coreceptor for viral entry. SDF1 inhibits HIV-1 infection by lymphocyte-tropic HIV-1 strains .
Cancer cells overexpress CXCR4 when compared to normal cells, and it is the most common chemokine receptor found on cancer cells. Its ligand CXCL12 is also found in the tumour micorenvironment . Expression of CXCR4 correlates with cancer cell metastasis, angiogenesis, and tumour growth . CXCR4 antagonists are predicted to exhibit anti-tumour activity via inhibition of CXCL12-CXCR4-mediated pro-survival signaling and chemotaxis . ",CXCR4 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. Due to its role in cancer cell homing and metastasis the CXCR4-CXCL12 axis is a potential target for cancer therapy . This is exemplified by the development of ulocuplumab as an anti-cancer biologic therapy. Targeting the CXCR4-CXCL12 axis also offers the possibility of modulating the immune response in non-cancer indications .
72,CXCR5,,"CXCR5 is reported to form functional heterodimers with Epstein-Barr virus-induced receptor 2 (EBI2, GPR183), with heterodimer formation down-modulating CXCR5-mediated responses .",CXCR5 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
73,CXCR6,,"",CXCR6 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. CXCR6 is upregulated by IL-2 and IL-15 .
74,CX3CR1,,,CX3CR1 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation.
75,XCR1,,,"XCR1 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. XCR1 is expressed by a subset of dendritic cells and along with its ligand 3647 (lymphotactin), is important for dendritic-cell-mediated cytotoxic immune responses and for the induction of self-tolerance and generation of Treg cells in the thymus."
78,CCRL2,,"A study of the haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes reveals a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21 . CCRL2 neither internalizes its ligands nor transduces signals, but presents bound ligands to functional signaling receptors improving their activity .
CCRL2-predicted hepatitis C treatment response to pegylated interferon and ribavirin therapy has been verified by RT-qPCR . ","CCRL2 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. However, the nomenclature of CCLR2 for this receptor and its classification as a member of the chemokine receptor family is provisional pending confirmation of chemokine binding. "
79,chemerin receptor 1,Chemerin1,"It is believed that another orphan receptor, CCLR2, may concentrate bioactive chemerin for presentation to the chemerin receptor .
The mouse and the two human splicing variants are 70% identical, the human splicing variants a and b showing 99% amino acid sequence identity. The mouse and the rat orthologues (the latter located to chromosome 12, region 12q16) display 91% identity . The promoter does not seem to be tissue specific but other elements or enhancers may be missing, and sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions . The murine receptor utilizes alternative promoters for transcription and is regulated by all-trans retinoic acid .
The chemerin receptor is a cell surface receptor that can be used to target recombinant adenovirus vectors to dendritic cells for vaccination development . HIV-1 subtype C lineages also had diverse alternative coreceptor patterns including the ability to use the chemerin receptor .
Chemerin and resolvin mediated divergent results suggesting the chemerin receptor is multifunctional . ","Studies in CMKLR1 (chemerin receptor 1) knockout mice highlight the role of this receptor in inflammation and obesity. Chemerin receptor 1 is activated by the lipid-derived, anti-inflammatory autacoid ligand resolvin E1. As its name suggests, reslovin E1 is involved in resolving physiological inflammatory responses. The metabolically stable resolvin E1 analogue, RX-10045 (navamepent) has completed Phase 2 clinical trials in several occular inflammation indications. In relation to multiple sclerosis (MS), clinical EAE is significantly reduced in CMKLR1 KO mice. Taking this in to consideration with data that confirm CMKLR1 expression by the main effector cells in MS, this protein is judged to be a novel and tractable target for therapeutic intervention in MS. CMKLR1 antagonists are being pursued as anti-inflammatory agents. The selective CMKLR1 antagonist CCX832 was developed by ChemoCentryx and GlaxoSmithKline as a potential anti-psoriatic medication, but development appears to have halted at Phase 1. is a CMKLR1 antagonist that has shown efficacious effects applicable to MS in vitro and in vivo ."
80,ACKR3,,"ACKR3 signals exclusively through β-arrestin-mediated pathways and does not activate canonical G protein signalling . It appears to act predominantly as a regulator of the chemokine network in developmental, homeostatic and infalmmatory processes, and in infection and cancer . CXCL11 and CXCL12 are ligands for ACKR3. Expression of ACKR3 is upregulated in some types of cancer making it a potential molecular target for drug development .","ACKR3 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. ACKR3 binds the chemokine CXCL12 (stromal cell-derived factor 1, SDF-1 which is also a ligand for CXCR4). ACKR3 is an atypical receptor in that it does not activate G-protein-mediated signaling but induces β-arrestin recruitment , and in heterodimers with CXCR4, regulates CXCL12-mediated G protein signaling . The ACKR3/CXCL12 axis is involved in physiological (developmental and regenerative) and pathological (regulation of cell growth, survival, adhesion, and invasion of many types of cancers and cytokine-driven angiogenesis) processes ."
81,GPR183,,"GPR183 is induced during Epstein-Barr Virus infection . The activity of GPR183 is regulated by at least two regions with PheVI:13 (Phe257) and the neighbouring residues acting as negative regulators, and ArgII:20 (Arg87)acting as a positive regulator . ",Gpr183-deficient mice show a reduction in the early antibody response to a T-dependent antigen. GPR183-deficient B cells fail to migrate to the outer follicle and instead stay in the follicle centre . This is suggested to position B cells in the correct location for mounting T-dependent antibody responses. GPR183 is induced during Epstein-Barr virus infection .
84,GPR4,,"The role of GPR4 as a proton-sensing receptor is supported by several publications .
Several studies state that GPR4 is a member of a GPCR orphan receptor subfamily with GPR65, GPR68 and GPR132 and that these receptors will be targets for the development of new anti-cancer small molecule drugs . There is an overlapping expression pattern between the members of this GPCR subfamily .
N-terminal histidine residues of the receptor are shown to be important in the receptor's function within certain pH ranges. It has been shown by mutagenesis experiments- His-174 and His-259 are conserved across this receptor subfamily and are required for the role in acid-sensing . The structural features essential for acid induction of inositol phosphate formation displayed by GPR68 are conserved in GPR4 suggesting a wider role for the receptor. CuCl2 binds to the conserved histidine residues in OGR1 therefor GPR4 may also be activated by CuCl2.
The broad expression pattern of GPR4 suggests its role as an acid-sensing receptor is involved in a wider range of physiological processes than the specific acid-sensing ion channels with an established role in nociception .
","GPR4 is a proton sensing GPCR with emerging roles in a range of physiological processes , including sensing and initiating responses to tissue acidosis. Pathophysiological states such as inflammation , tumours, ischemia, metabolic, and respiratory disease are commonly accompanied by tissue acidosis. Activation of GPR4 at acid pH stimulates the expression of inflammatory modulators such as chemokines, cytokines, and adhesion molecules, which significantly impacts cellular and humoural immune functions . Both pharmacological and genetic disruption of GPR4 produce broadly anti-inflammatory effects , adding further evidence that GPR4 is a pro-inflammatory GPCR. Thus, antagonists are being developed to test the validity of GPR4 blockade as a therapeutically effective mechanism to treat inflammatory conditions."
87,GPR15,,"The mouse orthologue of gpr15 can be induced by dioxin .
It has been reported in several studies that GPR15 acts as a co-receptor for HIV, and is used by HIV-2 strains . 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 , while others showing it is used by some strains but the significance of its use in relation to other coreceptors is unclear . R5X4 HIV-1 strains have been shown to use GPR15 as a coreceptor . 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 . 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 .
GPR15 is also a co-receptor for primary SIV strains . This has been demonstrated using GHOST and U87 cell line assays . 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 . 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 . A high degree of sequence similarity has been shown between the human and Rhesus macaque receptors . 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 . SIV strains SIVmac251 and SIVmac239 has been shown to utilise GPR15 as a coreceptor , and other SIVmac strains show preferential use of GPR15 over other coreceptors . A macrophage-tropic SIVMne clone was shown to use GPR15 as a coreceptor . Envelope proteins from HIV and SIV strains have been found to utilise GPR15 to enable their entry into cells , and that cell entry via fusion with GPR15 is CD4-dependent . However, a more recent study has shown GPR15 to have a role in CD4-independent cell entry . Eight HIV-1 envelope glycoproteins can use GPR15 to enable cell entry . SIV/17E-Fr, SIV/B670-Cl 3, and SIVsmE543 envelope proteins may mediate fusion with cells expressing CD4 and GPR15 . It is speculated that variation in the expression pattern of GPR15 may be a contributing factor in determining the outcome of SIV infection . 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 .
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 . 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 and by the use of amino acid substitutions in the SIV Env protein by Meister et al . Their results show that GPR15-utilisation can be impaired by a L320K-P321R substitution 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 . The importance of the V3 loop is confirmed by .
There is a high degree of sequence similarity between human and monkey receptors GPR15 receptors 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 .
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 . 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 . GPR15 was later shown to have high sequence similarity to GPR25 .
Changes in DNA methylation of 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 . 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 .