Details for: GNRHR

Gene ID: 2798

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: GNRHR

Ensembl ID: ENSG00000109163

Description: gonadotropin releasing hormone receptor

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 14.02
    rCSI 16.99%
    PRS 89.69
  • innate lymphoid cell CL0001065
    CSI 13.49
    rCSI 27.85%
    PRS 95.5
  • basal cell of epidermis CL0002187
    CSI 3.79
    rCSI 6.71%
    PRS 85.95
  • melanocyte of skin CL1000458
    CSI 2.52
    rCSI 3.43%
    PRS 86.95
  • suprabasal keratinocyte CL4033013
    CSI 1.35
    rCSI 2.2%
    PRS 87.78

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

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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 The [GNRHR](/details-gene/2798) gene encodes the gonadotropin-releasing hormone receptor, a member of the G protein-coupled receptor family. Canonically, this receptor is known for its essential role in the pituitary gland, where it binds gonadotropin-releasing hormone (GnRH) to regulate the synthesis and secretion of gonadotropins, thereby controlling reproductive function ([Link](https://doi.org/10.1016/0006-291x(92)91556-6)). Mutations in this gene are associated with idiopathic hypogonadotropic hypogonadism, a condition characterized by failed puberty and infertility ([Link](https://doi.org/10.1056/nejm199711273372205); [OMIM:153245](https://omim.org/entry/153245)). While its role in the neuroendocrine axis is well-established, expression data indicates a surprisingly high significance in specific immune cell populations, particularly `[CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203)` and `[innate lymphoid cells](/details-cell/CL0001065)`. This suggests that [GNRHR](/details-gene/2798) may have non-canonical functions in modulating adaptive and innate immunity. ## Cellular Roles and Expression Landscape The expression profile of [GNRHR](/details-gene/2798) reveals significant roles beyond its classical pituitary function. **Overall**, the gene shows its highest significance in distinct lymphocyte populations, suggesting a key role in immunomodulation. It is a top marker for `[CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203)` (CSI: 14.02) and `[innate lymphoid cells](/details-cell/CL0001065)` (CSI: 13.49). This high specificity suggests that GnRH signaling may directly influence the function or maintenance of these critical immune effectors. In addition to its role in the immune system, [GNRHR](/details-gene/2798) also shows moderate significance in several cell types within the skin. These include `[basal cell of epidermis](/details-cell/CL0002187)` (CSI: 3.79), `[melanocyte of skin](/details-cell/CL1000458)` (CSI: 2.52), and `[suprabasal keratinocyte](/details-cell/CL4033013)` (CSI: 1.35). This pattern is consistent with previous findings of [GNRHR](/details-gene/2798) expression in extrapituitary tissues and may indicate a function in local autocrine or paracrine signaling related to skin homeostasis, proliferation, or pigmentation. The co-expression in both immune and epidermal compartments points to a potential role at the interface of neuroendocrine and immune systems in peripheral tissues. ## Pathways and Molecular Function The molecular function of [GNRHR](/details-gene/2798) is centered on its activity as a G protein-coupled receptor. As annotated by the Gene Ontology, it possesses '[Gonadotropin-releasing hormone receptor activity](/details-go/GO:0004968)' and is an integral component of the '[plasma membrane](/details-go/GO:0005886)'. Its activation triggers the '[G protein-coupled receptor signaling pathway](/details-go/GO:0007186)', specifically leading to a '[cellular response to gonadotropin-releasing hormone](/details-go/GO:0097211)'. Reactome pathway analysis further refines this, placing it within '[Class a/1 (rhodopsin-like receptors)](https://reactome.org/content/detail/R-HSA-373076)' and highlighting its role in '[G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476)'. This signaling cascade is canonically linked to '[Gonadotropin secretion](/details-go/GO:0032274)' in pituitary gonadotropes. The high expression of [GNRHR](/details-gene/2798) in T cells and innate lymphoid cells implies that this same G-alpha(q) signaling machinery could be co-opted in these lymphocytes to regulate effector functions, such as cytokine release, proliferation, or cytotoxicity, in response to GnRH. ## Research Directions The unexpected high significance of [GNRHR](/details-gene/2798) in memory T cells and innate lymphoid cells opens up new avenues for research into neuro-immune interactions. While its role in reproductive endocrinology is well-defined, its function in the immune system remains largely unexplored. **Proposed Hypotheses:** 1. Signaling through [GNRHR](/details-gene/2798) directly modulates the survival, reactivation, and effector function of `[CD8-positive, alpha-beta memory T cells, CD45RO-positive](/details-cell/CL0001203)`. This could represent a direct mechanism by which the neuroendocrine system, particularly under conditions of stress or hormonal fluctuation, influences long-term adaptive immunity. 2. In `[innate lymphoid cells](/details-cell/CL0001065)`, which are key regulators of mucosal immunity, [GNRHR](/details-gene/2798) activation by local or systemic GnRH fine-tunes their cytokine production profile, thereby shaping the early response to pathogens or tissue damage. 3. The expression of [GNRHR](/details-gene/2798) in epidermal cells facilitates a local signaling network where GnRH, possibly produced locally, regulates keratinocyte proliferation and melanocyte function, contributing to skin homeostasis. **Key Experimental Approach:** To test the hypothesis that [GNRHR](/details-gene/2798) modulates memory T cell function, primary human `[CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203)` could be isolated and cultured. Following T cell receptor stimulation *in vitro*, cells would be treated with a specific GnRH agonist (e.g., leuprolide) or antagonist (e.g., cetrorelix). The functional consequences could be assessed by measuring proliferation via CFSE dilution, cytokine production (e.g., IFN-γ, TNF-α) by intracellular flow cytometry or ELISA, and cytotoxic potential through analysis of granzyme B and perforin expression. This would provide direct evidence for a functional role of [GNRHR](/details-gene/2798) in this specific immune cell subset. **Therapeutic Potential:** As a G protein-coupled receptor, [GNRHR](/details-gene/2798) is a highly druggable target, with well-established agonists and antagonists already in clinical use for reproductive disorders and hormone-dependent cancers. The findings of its high significance in immune cells suggest these existing drugs may have unappreciated immunomodulatory side effects. This also raises the possibility of repurposing GnRH receptor modulators for immunological applications. For example, [GNRHR](/details-gene/2798) antagonists could potentially be used to dampen specific T-cell-mediated autoimmune responses, while agonists might be explored to enhance immune responses in contexts like vaccination or cancer immunotherapy. Further investigation into the precise downstream effects of [GNRHR](/details-gene/2798) signaling in immune cells is critical to evaluating its potential as a therapeutic target for immunological disorders.

Genular Protein ID: 3653849089

Symbol: GNRHR_HUMAN

Name: Gonadotropin-releasing hormone receptor

UniProtKB Accession Codes:

P30968 O75793 Q14D13 Q92644

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 18 DrugCentral 1 EMBL 11 Ensembl 2 GO 7 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 1 PRINTS 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 RNAct 1 Reactome 2 RefSeq 2 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 1333190

Title: Cloning, sequencing, and expression of human gonadotropin releasing hormone (GnRH) receptor.

PubMed ID: 1333190

DOI: 10.1016/0006-291x(92)91556-6

PubMed ID: 8386108

Title: Cloning and characterization of the human GnRH receptor.

PubMed ID: 8386108

DOI: 10.1016/0303-7207(93)90278-r

PubMed ID: 7534732

Title: The nucleotide sequences of human GnRH receptors in breast and ovarian tumors are identical with that found in pituitary.

PubMed ID: 7534732

DOI: 10.1016/0303-7207(94)90196-1

PubMed ID: 9272108

Title: Molecular structure of the human gonadotropin-releasing hormone receptor gene.

PubMed ID: 9272108

DOI: 10.1530/eje.0.1370183

PubMed ID: 9259321

Title: Inhibition of gonadotropin-releasing hormone receptor signaling by expression of a splice variant of the human receptor.

PubMed ID: 9259321

DOI: 10.1210/mend.11.9.9966

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: 10366411

Title: Tissue-specific pattern of variant transcripts of the human gonadotropin-releasing hormone receptor gene.

PubMed ID: 10366411

DOI: 10.1530/eje.0.1400561

PubMed ID: 9371856

Title: A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor.

PubMed ID: 9371856

DOI: 10.1056/nejm199711273372205

PubMed ID: 9425890

Title: Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism.

PubMed ID: 9425890

DOI: 10.1038/ng0198-14

PubMed ID: 10022417

Title: The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred.

PubMed ID: 10022417

DOI: 10.1210/jcem.84.2.5449

PubMed ID: 10084584

Title: Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration.

PubMed ID: 10084584

DOI: 10.1210/jcem.84.3.5518

PubMed ID: 10523035

Title: Complete hypogonadotropic hypogonadism associated with a novel inactivating mutation of the gonadotropin-releasing hormone receptor.

PubMed ID: 10523035

DOI: 10.1210/jcem.84.10.6042

PubMed ID: 11397842

Title: The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism: spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor.

PubMed ID: 11397842

DOI: 10.1210/jcem.86.6.7542

PubMed ID: 11318785

Title: A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene.

PubMed ID: 11318785

DOI: 10.1046/j.1365-2265.2001.01211.x

PubMed ID: 11397871

Title: Two novel mutations in the gonadotropin-releasing hormone receptor gene in Brazilian patients with hypogonadotropic hypogonadism and normal olfaction.

PubMed ID: 11397871

DOI: 10.1210/jcem.86.6.7551

PubMed ID: 11994356

Title: Molecular basis of hypogonadotropic hypogonadism: restoration of mutant (E(90)K) GnRH receptor function by a deletion at a distant site.

PubMed ID: 11994356

DOI: 10.1210/jcem.87.5.8386

PubMed ID: 12679486

Title: Mutation Ala(171)Thr stabilizes the gonadotropin-releasing hormone receptor in its inactive conformation, causing familial hypogonadotropic hypogonadism.

PubMed ID: 12679486

DOI: 10.1210/jc.2002-020005

PubMed ID: 23643382

Title: Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.

PubMed ID: 23643382

DOI: 10.1016/j.ajhg.2013.04.008

PubMed ID: 25077900

Title: The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.

PubMed ID: 25077900

DOI: 10.1210/jc.2014-2110

Sequence Information:

  • Length: 328
  • Mass: 37731
  • Checksum: D02B2EA2F4246D7B
  • Sequence:
    • MANSASPEQN QNHCSAINNS IPLMQGNLPT LTLSGKIRVT VTFFLFLLSA TFNASFLLKL 
QKWTQKKEKG KKLSRMKLLL KHLTLANLLE TLIVMPLDGM WNITVQWYAG ELLCKVLSYL 
KLFSMYAPAF MMVVISLDRS LAITRPLALK SNSKVGQSMV GLAWILSSVF AGPQLYIFRM 
IHLADSSGQT KVFSQCVTHC SFSQWWHQAF YNFFTFSCLF IIPLFIMLIC NAKIIFTLTR 
VLHQDPHELQ LNQSKNNIPR ARLKTLKMTV AFATSFTVCW TPYYVLGIWY WFDPEMLNRL 
SDPVNHFFFL FAFLNPCFDP LIYGYFSL