Details for: GPR65

Gene ID: 8477

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: GPR65

Ensembl ID: ENSG00000140030

Description: G protein-coupled receptor 65

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • basophil CL0000767
    CSI 22.7
    rCSI 48.03%
    PRS 35.48
  • natural T-regulatory cell CL0000903
    CSI 22.61
    rCSI 42.83%
    PRS 46.95
  • plasmacytoid dendritic cell, human CL0001058
    CSI 20.93
    rCSI 14.62%
    PRS 18.88
  • T-helper 17 cell CL0000899
    CSI 17.54
    rCSI 13.92%
    PRS 31.48
  • memory T cell CL0000813
    CSI 16.34
    rCSI 31.48%
    PRS 39.57
  • activated type II NK T cell CL0000931
    CSI 12.69
    rCSI 14.28%
    PRS 28.48
  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 10.36
    rCSI 20.65%
    PRS 29.83
  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 5.83
    rCSI 3.93%
    PRS 21.61
  • early lymphoid progenitor CL0000936
    CSI 5.74
    rCSI 5.04%
    PRS 20.36
  • group 2 innate lymphoid cell CL0001069
    CSI 5.49
    rCSI 29.71%
    PRS 55.92
  • granulocyte CL0000094
    CSI 4.64
    rCSI 7.09%
    PRS 22.84
  • neutrophil CL0000775
    CSI 4.6
    rCSI 25.73%
    PRS 33.92
  • mast cell CL0000097
    CSI 3.75
    rCSI 8.1%
    PRS 63.39
  • eosinophil CL0000771
    CSI 3.4
    rCSI 22.3%
    PRS 44.52
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 3.34
    rCSI 5.72%
    PRS 35.03
  • CD4-positive, alpha-beta thymocyte CL0000810
    CSI 2.8
    rCSI 2.24%
    PRS 31.75
  • dendritic cell, human CL0001056
    CSI 2.44
    rCSI 3.74%
    PRS 21.15
  • alternatively activated macrophage CL0000890
    CSI 2.41
    rCSI 3.03%
    PRS 27.32
  • mature NK T cell CL0000814
    CSI 2.24
    rCSI 2.86%
    PRS 61.65
  • myeloid dendritic cell CL0000782
    CSI 2.07
    rCSI 3%
    PRS 26.61
  • group 3 innate lymphoid cell CL0001071
    CSI 1.62
    rCSI 1.22%
    PRS 18.76
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 1.6
    rCSI 1.57%
    PRS 27.78
  • T-helper 1 cell CL0000545
    CSI 1.46
    rCSI 2.63%
    PRS 44.17
  • mononuclear phagocyte CL0000113
    CSI 1.45
    rCSI 3.19%
    PRS 19.96
  • activated CD8-positive, alpha-beta T cell CL0000906
    CSI 1.38
    rCSI 1.35%
    PRS 48.24
  • mucosal invariant T cell CL0000940
    CSI 1.35
    rCSI 1.09%
    PRS 27.91
  • inflammatory macrophage CL0000863
    CSI 1.32
    rCSI 2.26%
    PRS 35.7
  • CD8-positive, alpha-beta thymocyte CL0000811
    CSI 1.31
    rCSI 2.05%
    PRS 41.16
  • unswitched memory B cell CL0000970
    CSI 1.27
    rCSI 1.07%
    PRS 28.33
  • non-classical monocyte CL0000875
    CSI 1.19
    rCSI 1.9%
    PRS 49.81
  • dendritic cell CL0000451
    CSI 1.16
    rCSI 1.43%
    PRS 51.43
  • mature alpha-beta T cell CL0000791
    CSI 1.08
    rCSI 3.91%
    PRS 30.42
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 1.06
    rCSI 0.8%
    PRS 23.39
  • common dendritic progenitor CL0001029
    CSI 1.03
    rCSI 1.29%
    PRS 22.98
  • innate lymphoid cell CL0001065
    CSI 1.02
    rCSI 2.1%
    PRS 26.65
  • erythrocyte CL0000232
    CSI 1
    rCSI 2.26%
    PRS 24.41
  • activated CD4-positive, alpha-beta T cell CL0000896
    CSI 0.99
    rCSI 0.91%
    PRS 32.07
  • mature T cell CL0002419
    CSI 0.82
    rCSI 0.64%
    PRS 25.91
  • intermediate monocyte CL0002393
    CSI 0.82
    rCSI 1.24%
    PRS 17.88
  • CD8-positive, alpha-beta memory T cell CL0000909
    CSI 0.79
    rCSI 0.83%
    PRS 49.65
  • intraepithelial lymphocyte CL0002496
    CSI 0.75
    rCSI 2.04%
    PRS 62.09
  • lung resident memory CD8-positive, alpha-beta T cell CL4033039
    CSI 0.74
    rCSI 1.92%
    PRS 44.19
  • helper T cell CL0000912
    CSI 0.74
    rCSI 1.05%
    PRS 24.57
  • CD16-negative, CD56-bright natural killer cell, human CL0000938
    CSI 0.73
    rCSI 0.54%
    PRS 48.6
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 0.72
    rCSI 0.56%
    PRS 16.38
  • double negative thymocyte CL0002489
    CSI 0.68
    rCSI 0.48%
    PRS 21.12
  • CD4-positive, alpha-beta cytotoxic T cell CL0000934
    CSI 0.67
    rCSI 0.92%
    PRS 35.77
  • CD4-positive helper T cell CL0000492
    CSI 0.65
    rCSI 0.49%
    PRS 24.44
  • effector memory CD8-positive, alpha-beta T cell CL0000913
    CSI 0.63
    rCSI 0.58%
    PRS 27.04
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 0.6
    rCSI 0.4%
    PRS 43.72
  • myeloid dendritic cell, human CL0001057
    CSI 0.59
    rCSI 3.31%
    PRS 53
  • monocyte CL0000576
    CSI 0.57
    rCSI 1.02%
    PRS 45.32
  • promonocyte CL0000559
    CSI 0.54
    rCSI 0.92%
    PRS 24.12
  • effector memory CD4-positive, alpha-beta T cell CL0000905
    CSI 0.52
    rCSI 0.7%
    PRS 41.68
  • macrophage CL0000235
    CSI 0.4
    rCSI 0.74%
    PRS 59.84
  • Kupffer cell CL0000091
    CSI 0.37
    rCSI 0.85%
    PRS 17.23
  • plasmablast CL0000980
    CSI 0.33
    rCSI 0.26%
    PRS 21.42
  • alveolar macrophage CL0000583
    CSI 0.3
    rCSI 0.49%
    PRS 20.95
  • class switched memory B cell CL0000972
    CSI 0.25
    rCSI 0.19%
    PRS 29.92
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 0.25
    rCSI 0.3%
    PRS 21.21
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 0.23
    rCSI 0.65%
    PRS 26.22
  • elicited macrophage CL0000861
    CSI 0.16
    rCSI 0.15%
    PRS 20.71
  • CD8-positive, alpha-beta cytotoxic T cell CL0000794
    CSI 0.16
    rCSI 0.19%
    PRS 31.01
  • Langerhans cell CL0000453
    CSI 0.13
    rCSI 0.2%
    PRS 31.24
  • mature B cell CL0000785
    CSI 0.12
    rCSI 0.1%
    PRS 22.19
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 0.11
    rCSI 0.54%
    PRS 23.46
  • CD34-positive, CD56-positive, CD117-positive common innate lymphoid precursor, human CL0001074
    CSI 0.1
    rCSI 1.11%
    PRS 60.62
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 0.06
    rCSI 0.07%
    PRS 22.46
  • Hofbauer cell CL3000001
    CSI 0.06
    rCSI 0.11%
    PRS 22.34
  • cytotoxic T cell CL0000910
    CSI 0.03
    rCSI 0.19%
    PRS 26.03
  • myeloid leukocyte CL0000766
    CSI -0.07
    rCSI -0.06%
    PRS 18.33
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI -0.14
    rCSI -0.1%
    PRS 24.37
  • alpha-beta T cell CL0000789
    CSI -0.61
    rCSI -0.71%
    PRS 24.03
  • lung macrophage CL1001603
    CSI -0.75
    rCSI -1.69%
    PRS 20.54
  • ependymal cell CL0000065
    CSI -1.48
    rCSI -3%
    PRS 8.57
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI -4.83
    rCSI -6.33%
    PRS 25.24

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [GPR65](/details-gene/8477), or G protein-coupled receptor 65, is a protein-coding gene located on chromosome 14. It functions as a proton-sensing receptor, activated by acidic pH, and is also recognized as a receptor for the lipid psychosine ([Link](https://doi.org/10.1083/jcb.153.2.429)). As a member of the rhodopsin-like GPCR family, it participates in G alpha (q) signaling pathways, influencing adenylate cyclase activity and apoptotic processes. Expression data reveals that [GPR65](/details-gene/8477) is a highly significant marker in various immune cell populations, particularly granulocytes such as [basophils](/details-cell/CL0000767), specific T cell subsets including [natural T-regulatory cells](/details-cell/CL0000903) and [T-helper 17 cells](/details-cell/CL0000899), and [plasmacytoid dendritic cells](/details-cell/CL0001058), suggesting a critical role in orchestrating immune responses in acidic microenvironments. ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [GPR65](/details-gene/8477) firmly establishes its importance within the immune system, with pronounced significance in both innate and adaptive lineages. The gene shows the highest significance in [basophils](/details-cell/CL0000767) (CSI: 22.70), a key cell type in allergic inflammatory responses. Its role in adaptive immunity is highlighted by very high significance in T cell subsets critical for immune regulation and inflammation, including [natural T-regulatory cells](/details-cell/CL0000903) (CSI: 22.61) and pro-inflammatory [T-helper 17 cells](/details-cell/CL0000899) (CSI: 17.54). Furthermore, its high significance in [plasmacytoid dendritic cells, human](/details-cell/CL0001058) (CSI: 20.93) points to a potential role in antiviral immunity and antigen presentation. The gene's expression extends to other important immune cells, including [memory T cells](/details-cell/CL0000813), [group 2 innate lymphoid cells](/details-cell/CL0001069), and other granulocytes like [neutrophils](/details-cell/CL0000775) and [eosinophils](/details-cell/CL0000771), underscoring a broad function in immune cell activity. Conversely, [GPR65](/details-gene/8477) shows very low or negative significance in [CD14-positive, CD16-positive monocytes](/details-cell/CL0002397) and non-hematopoietic cells like [ependymal cells](/details-cell/CL0000065). This selective expression pattern suggests that [GPR65](/details-gene/8477) is not a pan-immune marker but rather a specialized receptor whose function is particularly relevant in specific immune effector and regulatory cells. ## Pathways and Molecular Function Functionally, [GPR65](/details-gene/8477) is annotated as a G protein-coupled receptor ([GO:0004930](https://www.ebi.ac.uk/QuickGO/term/GO:0004930)) located on the plasma membrane ([GO:0005886](https://www.ebi.ac.uk/QuickGO/term/GO:0005886)). It operates within the [Class a/1 (rhodopsin-like receptors)](https://reactome.org/content/detail/R-HSA-373076) family and is integral to [Gpcr downstream signalling](https://reactome.org/content/detail/R-HSA-388396), particularly through [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476). A key biological process associated with [GPR65](/details-gene/8477) is the [response to acidic ph](https://www.ebi.ac.uk/QuickGO/term/GO:0010447), which is highly relevant to its expression in immune cells that often function within inflamed, acidic tissue microenvironments. Research has demonstrated that a genetic variant in [GPR65](/details-gene/8477) alters lysosomal pH and is linked to an increased risk for colitis, highlighting a direct connection between its pH-sensing function and inflammatory disease ([Link](https://doi.org/10.1016/j.immuni.2016.05.007)). This function is consistent with its high expression in [T-helper 17 cells](/details-cell/CL0000899) and regulatory T cells, which are known to be key cellular players in inflammatory bowel disease. The receptor's involvement in the [apoptotic process](https://www.ebi.ac.uk/QuickGO/term/GO:0006915) was also suggested in early studies ([Link](https://doi.org/10.1089/dna.1998.17.493)). ## Research Directions The specific expression pattern of [GPR65](/details-gene/8477) in key immune cell subsets, combined with its function as a proton sensor, suggests it acts as a crucial regulator of immune cell function in pathological microenvironments like tumors or sites of chronic inflammation. ### Proposed Hypotheses: 1. **Hypothesis:** Given its high significance in both pro-inflammatory [T-helper 17 cells](/details-cell/CL0000899) and anti-inflammatory [natural T-regulatory cells](/details-cell/CL0000903), [GPR65](/details-gene/8477) signaling in response to local acidic pH may act as a critical switch that dictates the differentiation and functional balance between these two opposing lineages, thereby shaping the outcome of autoimmune diseases and anti-tumor responses. 2. **Hypothesis:** The high expression of [GPR65](/details-gene/8477) on [basophils](/details-cell/CL0000767) and [mast cells](/details-cell/CL0000097) suggests that proton sensing via this receptor is a key mechanism for the activation and degranulation of these cells during the acute phase of allergic reactions, where tissue acidosis can occur. ### Experimental Approach: To test the first hypothesis regarding the role of [GPR65](/details-gene/8477) in T cell fate decisions, a definitive experiment would involve genetic manipulation. Naive CD4+ T cells could be isolated from both wild-type and [GPR65](/details-gene/8477)-knockout mice. These cells would then be cultured under polarizing conditions for Th17 (e.g., TGF-β, IL-6) and Treg (e.g., TGF-β, IL-2) differentiation across a range of acidic (e.g., pH 6.5-7.0) and physiological (pH 7.4) pH levels. The differentiation efficiency could be quantified by flow cytometric analysis of key transcription factors (RORγt for Th17, FoxP3 for Treg), and functional output could be measured by assessing cytokine secretion (IL-17, IL-10) via ELISA or multiplex assay. A significant difference in the ratio of Th17 to Treg cells between wild-type and knockout conditions, particularly at acidic pH, would confirm the role of [GPR65](/details-gene/8477) as a key environmental sensor in this process. ### Therapeutic Potential: As a cell-surface G protein-coupled receptor, [GPR65](/details-gene/8477) is a highly druggable target. Its established link to inflammatory bowel disease ([Link](https://doi.org/10.1016/j.immuni.2016.05.007)) and its high expression on key inflammatory cell types make it a compelling target for therapeutic intervention. The development of small molecule antagonists or neutralizing antibodies targeting [GPR65](/details-gene/8477) could represent a novel strategy for treating autoimmune and inflammatory disorders. Inhibition of [GPR65](/details-gene/8477) could dampen the pro-inflammatory activity of cells like [T-helper 17 cells](/details-cell/CL0000899) in acidic tissue environments, thereby alleviating pathology while potentially having limited effects in healthy tissues where pH is physiological.

Genular Protein ID: 616454139

Symbol: PSYR_HUMAN

Name: Psychosine receptor

UniProtKB Accession Codes:

Q8IYL9 O75819

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 4 Ensembl 1 ExpressionAtlas 1 GO 11 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9655242

Title: Cloning, characterization, and mapping of human homolog of mouse T-cell death-associated gene.

PubMed ID: 9655242

DOI: 10.1089/dna.1998.17.493

PubMed ID: 12508121

Title: The DNA sequence and analysis of human chromosome 14.

PubMed ID: 12508121

DOI: 10.1038/nature01348

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 11309421

Title: Identification of a molecular target of psychosine and its role in globoid cell formation.

PubMed ID: 11309421

DOI: 10.1083/jcb.153.2.429

PubMed ID: 27287411

Title: Genetic coding variant in GPR65 alters lysosomal pH and links lysosomal dysfunction with colitis risk.

PubMed ID: 27287411

DOI: 10.1016/j.immuni.2016.05.007

Sequence Information:

  • Length: 337
  • Mass: 39333
  • Checksum: CFDBF217291C0FA2
  • Sequence:
    • MNSTCIEEQH DLDHYLFPIV YIFVIIVSIP ANIGSLCVSF LQAKKESELG IYLFSLSLSD 
LLYALTLPLW IDYTWNKDNW TFSPALCKGS AFLMYMNFYS STAFLTCIAV DRYLAVVYPL 
KFFFLRTRRF ALMVSLSIWI LETIFNAVML WEDETVVEYC DAEKSNFTLC YDKYPLEKWQ 
INLNLFRTCT GYAIPLVTIL ICNRKVYQAV RHNKATENKE KKRIIKLLVS ITVTFVLCFT 
PFHVMLLIRC ILEHAVNFED HSNSGKRTYT MYRITVALTS LNCVADPILY CFVTETGRYD 
MWNILKFCTG RCNTSQRQRK RILSVSTKDT MELEVLE