GO:0045745 positive regulation of G protein-coupled receptor signaling pathway: Signaling Amplification, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0045745 describes any process that activates or increases the frequency, rate or extent of G protein-coupled receptor (GPCR) signaling pathway activity.
• Positive regulation of GPCR signaling is essential for diverse physiological processes including bone homeostasis, intestinal regeneration, immune tolerance, and kidney protection [1,2,3,5].
• GPCR signaling can be positively regulated by allosteric modulators that stabilize megacomplexes of receptor, G protein, and beta-arrestin, as shown for a versatile allosteric modulator.
• Dysregulated positive regulation of GPCR signaling contributes to diabetic kidney disease, colitis, metabolic dysfunction-associated steatohepatitis, and bone metastasis [1,3,4,8].
• Key genes involved include ADGRG6, GPR124, GPR120, GPR91, TGR5, GPR31, LGR4, and RSPO2, each with distinct roles in tissue homeostasis and disease [1,2,3,4,5,6,8].
• CRISPR-based knockout, knock-in, point mutation, and overexpression models are powerful tools to dissect the causal roles of these genes in GPCR signaling [1,2,3,4,5,6,7,8].
Description
G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and mediate cellular responses to a wide array of extracellular stimuli. The Gene Ontology term GO:0045745, positive regulation of G protein-coupled receptor signaling pathway, encompasses any process that activates or increases the frequency, rate or extent of GPCR signaling activity. This term is critical for understanding how cells amplify and sustain GPCR-mediated signals, which are fundamental to physiology and disease. Recent studies have identified diverse mechanisms that positively regulate GPCR signaling, including allosteric modulation that stabilizes receptor-G protein-beta-arrestin megacomplexes. The importance of this regulatory process is underscored by its involvement in bone homeostasis, where ADGRG6 maintains growth plate homeostasis through IHH signaling, and in kidney protection, where GPR124 prevents podocyte senescence and injury in diabetic kidney disease. Positive regulation of GPCR signaling also plays key roles in immune regulation, as GPR120 inhibits colitis through regulation of CD4+ T cell interleukin 10 production. These examples highlight the broad physiological relevance of this GO term. Understanding the molecular players and mechanisms that positively regulate GPCR signaling is essential for developing targeted therapies for diseases ranging from metabolic disorders to cancer. This article synthesizes current knowledge on GO:0045745, covering its definition, core mechanisms, key genes, disease associations, and research methodologies, with a focus on CRISPR-based approaches for functional validation.
positive regulation of G protein-coupled receptor signaling pathway At A Glance
| GO ID | GO:0045745 |
|---|---|
| GO term | positive regulation of G protein-coupled receptor signaling pathway |
| Ontology | biological_process |
| Synonym | activation of G-protein coupled receptor protein signaling pathway; positive regulation of GPCR protein signaling pathway; stimulation of G-protein coupled receptor protein signaling pathway; upregulation of G-protein coupled receptor protein signaling pathway |
| Major function | Enhances the frequency, rate, or extent of GPCR signaling, leading to amplified downstream cellular responses. |
| Related processes | GPCR signaling pathway (GO:0007186), negative regulation of GPCR signaling (GO:0045744), G protein-coupled receptor activity (GO:0004930). |
| Cellular location | Plasma membrane, endosomes, and other membrane compartments where GPCRs and their regulators reside. |
| Key regulators | Allosteric modulators, G proteins, beta-arrestins, receptor kinases, and accessory proteins. |
What Is GO:0045745?
GO:0045745, positive regulation of G protein-coupled receptor signaling pathway, is a biological process defined as any process that activates or increases the frequency, rate or extent of G protein-coupled receptor signaling pathway activity. In simpler terms, it includes all molecular events that enhance or sustain the signal transmitted from a GPCR to downstream effectors. This regulation can occur at multiple levels, including ligand availability, receptor conformational changes, G protein coupling efficiency, and interactions with accessory proteins such as beta-arrestins. The term is distinct from negative regulation (GO:0045744) and encompasses both direct and indirect mechanisms that amplify GPCR signaling output.
Why Is positive regulation of G protein-coupled receptor signaling pathway Important in Cell Biology?
Positive regulation of GPCR signaling is fundamental to physiology because it determines the magnitude and duration of cellular responses to hormones, neurotransmitters, and other ligands. Dysregulation of this process is implicated in numerous diseases, including diabetic kidney disease, inflammatory bowel disease, metabolic liver disease, and bone disorders [1,3,4,8]. Understanding the mechanisms that positively regulate GPCR signaling can reveal therapeutic targets for enhancing beneficial signaling or inhibiting pathological overactivation. Moreover, GPCRs are the targets of approximately one-third of all approved drugs, making the study of their positive regulation highly relevant for pharmacology and drug discovery.
• Critical for bone homeostasis and growth plate development through ADGRG6 and IHH signaling.
• Protects against diabetic kidney disease by preventing podocyte senescence via GPR124.
• Suppresses colitis by promoting IL-10 production in CD4+ T cells through GPR120.
• Drives intestinal stem cell activation and epithelial regeneration via TGR5.
• Contributes to metabolic dysfunction-associated steatohepatitis (MASH) fibrosis through succinate-GPR91 signaling.
• Regulates bone metastasis by mediating RSPO2 and RANKL signaling through LGR4.
• Involved in bone homeostasis via Pla2g7-Alox12-12-HETE-Gpr31 axis.
• Allosteric modulators can stabilize GPCR-G protein-beta-arrestin megacomplexes, enhancing signaling.
• Provides targets for therapeutic intervention in cancer, inflammation, and metabolic diseases [1,3,4,8].
• Essential for understanding drug efficacy and resistance mechanisms for GPCR-targeted therapies.
What Happens During positive regulation of G protein-coupled receptor signaling pathway?
Ligand binding and receptor activation
In simple terms: A signal molecule binds to the GPCR, causing the receptor to change shape and become active.
The first step in positive regulation of GPCR signaling is the binding of an agonist ligand to the receptor, which stabilizes an active conformation. This conformational change allows the receptor to act as a guanine nucleotide exchange factor for heterotrimeric G proteins. Recent structural studies have revealed that allosteric modulators can further enhance this process by stabilizing a megacomplex comprising the receptor, G protein, and beta-arrestin. This megacomplex formation represents a key mechanism for positive regulation, as it prolongs and amplifies downstream signaling.
G protein activation and effector engagement
In simple terms: The activated receptor turns on G proteins, which then trigger various signaling cascades inside the cell.
Upon activation, the GPCR catalyzes the exchange of GDP for GTP on the G alpha subunit, leading to dissociation of G alpha from G beta-gamma dimers. Both subunits can then engage downstream effectors such as adenylyl cyclase, phospholipase C, and ion channels. Positive regulation can occur through enhanced coupling efficiency or increased availability of G proteins. For example, ADGRG6 maintains growth plate homeostasis through IHH signaling, which involves G protein-dependent pathways. Similarly, GPR124 protects podocytes by positively regulating signaling that counteracts senescence.
Beta-arrestin recruitment and megacomplex formation
In simple terms: Beta-arrestin proteins can bind to the active receptor and act as scaffolds that enhance or redirect signaling.
Beta-arrestins are traditionally known for desensitizing GPCRs, but they can also positively regulate signaling by serving as scaffolds for kinases and other effectors. A recent study demonstrated that a versatile allosteric modulator enables the formation of a GPCR-G protein-beta-arrestin megacomplex, which sustains signaling. This megacomplex represents a novel paradigm for positive regulation, where beta-arrestin is not merely a terminator but an amplifier. Such mechanisms are critical for fine-tuning cellular responses to hormones and neurotransmitters.
Downstream amplification and cellular responses
In simple terms: The initial signal is amplified through second messengers and kinase cascades, leading to changes in cell behavior.
Positive regulation of GPCR signaling ultimately leads to amplified downstream responses, such as increased cyclic AMP production, calcium mobilization, or activation of MAPK pathways. These responses drive physiological outcomes like bone remodeling, immune tolerance, and tissue regeneration. For instance, TGR5 activation by bile acids promotes intestinal stem cell activation and epithelial regeneration. In contrast, dysregulated positive regulation can contribute to pathology, as seen in MASH fibrosis driven by succinate-GPR91 signaling and in bone metastasis mediated by LGR4.
Key Genes Involved in GO:0045745 positive regulation of G protein-coupled receptor signaling pathway
The following genes and proteins are key players in positively regulating GPCR signaling pathways, as supported by recent literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| GPR124 | Protects podocytes from senescence and injury | Diabetic kidney disease model; KO and overexpression studies |
| ADGRG6 | Maintains growth plate homeostasis via IHH signaling | Bone development; KO mouse models |
| GPR120 | Inhibits colitis by promoting IL-10 in CD4+ T cells | Inflammatory bowel disease; KO and agonist studies |
| GPR91 | Mediates succinate signaling in hepatic stellate cells | MASH fibrosis; KO and pharmacological inhibition |
| TGR5 | Activates intestinal stem cells and epithelial regeneration | Intestinal regeneration; KO and agonist studies |
| GPR31 | Mediates 12-HETE signaling in bone homeostasis | Bone metabolism; KO and knock-in models |
| LGR4 | Regulates osteoclastic premetastatic niche and bone metastasis | Bone metastasis; KO and overexpression |
| RSPO2 | Ligand for LGR4 in bone metastasis | Bone metastasis; KO and knock-in |
| RANKL | Ligand for LGR4 in osteoclast regulation | Bone metastasis; KO and knock-in |
| Beta-arrestin | Scaffold in GPCR-G protein megacomplex | Allosteric modulation; KO and tagged knock-in |
| G alpha subunits | Transduce signals from activated GPCRs | GPCR signaling; KO and point mutation |
| Pla2g7 | Regulates bone homeostasis via Alox12/12-HETE/Gpr31 | Bone homeostasis; KO models |
| Alox12 | Produces 12-HETE for Gpr31 signaling | Bone homeostasis; KO models |
| GPR124 | Podocyte protection in diabetic kidney disease | Kidney disease; KO and overexpression |
| ADGRG6 | Chondrocyte regulation via IHH | Growth plate; KO and knock-in |
| GPR120 | Immune regulation in colitis | Colitis; KO and agonist |
| TGR5 | Bile acid receptor in intestinal stem cells | Regeneration; KO and agonist |
How Is positive regulation of G protein-coupled receptor signaling pathway Regulated?
Positive regulation of GPCR signaling is itself subject to multiple layers of regulation. Allosteric modulators can enhance the formation of GPCR-G protein-beta-arrestin megacomplexes, thereby amplifying signaling. Additionally, the availability of ligands, such as bile acids for TGR5 or succinate for GPR91, directly influences the extent of receptor activation. Post-translational modifications of GPCRs, including phosphorylation and ubiquitination, can modulate their activity and trafficking. Furthermore, accessory proteins like RSPO2 can potentiate signaling through LGR4 in bone metastasis. These regulatory mechanisms ensure that GPCR signaling is tightly controlled in a context-dependent manner.
positive regulation of G protein-coupled receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GPR124 | Diabetic kidney disease | Podocyte-specific KO and overexpression in mice |
| GPR120 | Colitis | CD4+ T cell-specific KO and agonist treatment |
| GPR91 | MASH fibrosis | Hepatic stellate cell-specific KO and pharmacological inhibition |
| LGR4 | Bone metastasis | Osteoclast-specific KO and knock-in |
| ADGRG6 | Growth plate disorders | Chondrocyte-specific KO and knock-in |
Diabetic kidney disease
GPR124 positively regulates GPCR signaling to protect podocytes from senescence and injury in diabetic kidney disease. Loss of GPR124 exacerbates podocyte damage, suggesting that enhancing its signaling could be therapeutic.
Inflammatory bowel disease
GPR120 activation inhibits colitis by promoting IL-10 production in CD4+ T cells. This positive regulation of GPCR signaling helps maintain immune tolerance in the gut.
Metabolic dysfunction-associated steatohepatitis (MASH)
Succinate-GPR91 signaling in hepatic stellate cells drives fibrotic progression in MASH. Blocking this pathway reduces fibrosis, indicating that positive regulation of GPR91 signaling is pathogenic in this context.
Bone metastasis
RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. Positive regulation of LGR4 signaling promotes metastatic bone disease.
From positive regulation of G protein-coupled receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does GPR124 protect against podocyte senescence? | Podocyte-specific GPR124 KO and overexpression |
| How does ADGRG6 regulate growth plate homeostasis? | Chondrocyte-specific ADGRG6 KO and knock-in |
| Can GPR120 activation suppress colitis? | CD4+ T cell-specific GPR120 KO and agonist treatment |
| Does GPR91 blockade reduce MASH fibrosis? | Hepatic stellate cell-specific GPR91 KO and inhibitor |
| What is the role of TGR5 in intestinal regeneration? | Intestinal stem cell-specific TGR5 KO and agonist |
| How does LGR4 mediate bone metastasis? | Osteoclast-specific LGR4 KO and knock-in |
How to Study the positive regulation of G protein-coupled receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function effects on GPCR signaling | Identify essential positive regulators [1,2,3] |
| CRISPR knock-in | Tagged receptor localization and function | Study receptor trafficking and megacomplex formation |
| RNA-seq | Transcriptional changes | Identify downstream targets of GPCR signaling [4,5] |
| Proteomics | Protein abundance and interactions | Map signaling complexes |
| cAMP assay | G protein activation | Quantify GPCR signaling strength |
| Beta-arrestin recruitment | Receptor desensitization and scaffolding | Measure positive regulation via beta-arrestin |
| Calcium imaging | Gq-coupled signaling | Assess GPCR activation in live cells |
| In vivo disease models | Pathological outcomes | Validate therapeutic targets [1,3,4,8] |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify genes that positively regulate GPCR signaling. For example, knocking out GPR124, ADGRG6, or GPR120 can reveal their essential roles in specific signaling pathways [1,2,3].
Transcriptomic and proteomic profiling
RNA-seq and proteomics can measure changes in gene expression and protein abundance upon modulation of GPCR signaling. These methods help identify downstream effectors and feedback regulators [4,5].
Functional assays for GPCR signaling
cAMP, calcium mobilization, and beta-arrestin recruitment assays are used to quantify GPCR signaling activity. These assays can be combined with CRISPR knock-in of tagged receptors for real-time monitoring.
In vivo disease models
Mouse models of diabetic kidney disease, colitis, MASH, and bone metastasis are used to study the role of positive regulation of GPCR signaling in disease pathogenesis [1,3,4,8].
How CRISPR Can Be Used to Study GO:0045745 positive regulation of G protein-coupled receptor signaling pathway
Knockout
CRISPR knockout of genes such as GPR124, ADGRG6, GPR120, GPR91, TGR5, GPR31, and LGR4 has been used to demonstrate their positive regulatory roles in GPCR signaling. For example, GPR124 knockout exacerbates podocyte injury in diabetic kidney disease, while ADGRG6 knockout disrupts growth plate homeostasis.
Point Mutation
Point mutations can be introduced to study specific residues critical for GPCR signaling. For instance, mutating phosphorylation sites in the receptor or G protein can reveal their role in positive regulation. Such models are valuable for dissecting allosteric modulation mechanisms.
Knock-in
Knock-in of tagged receptors or reporters allows real-time monitoring of GPCR signaling. Tagged beta-arrestin or G protein knock-in mice can be used to visualize megacomplex formation and trafficking in vivo.
Overexpression
Overexpression of positive regulators such as GPR124 or GPR120 can enhance GPCR signaling and protect against disease. Overexpression models are useful for testing therapeutic potential of enhancing GPCR signaling [1,3].
How EDITGENE Supports positive regulation of G protein-coupled receptor signaling pathway Research
Researchers studying positive regulation of G protein-coupled receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in enhancing GPCR signaling. EDITGENE provides comprehensive CRISPR-based services to generate knockout, point mutation, knock-in, and overexpression cell models, as well as CRISPR library screening and bioinformatics support, enabling precise functional dissection of GPCR regulatory networks.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of G protein-coupled receptor signaling pathway research.
Frequently Asked Questions About positive regulation of G protein-coupled receptor signaling pathway
What is GO:0045745?
GO:0045745 is the Gene Ontology term for positive regulation of G protein-coupled receptor signaling pathway, defined as any process that activates or increases the frequency, rate or extent of GPCR signaling activity.
What genes are involved in positive regulation of GPCR signaling?
Key genes include GPR124, ADGRG6, GPR120, GPR91, TGR5, GPR31, LGR4, RSPO2, and RANKL, among others [1,2,3,4,5,6,8].
How does positive regulation of GPCR signaling work?
It involves ligand binding, receptor activation, G protein coupling, beta-arrestin recruitment, and formation of megacomplexes that amplify downstream signals.
What diseases are associated with positive regulation of GPCR signaling?
Diseases include diabetic kidney disease, colitis, MASH fibrosis, bone metastasis, and growth plate disorders [1,2,3,4,8].
What is the role of beta-arrestin in positive regulation of GPCR signaling?
Beta-arrestin can act as a scaffold in GPCR-G protein-beta-arrestin megacomplexes, enhancing rather than terminating signaling.
How can CRISPR be used to study positive regulation of GPCR signaling?
CRISPR knockout, knock-in, point mutation, and overexpression models allow functional dissection of GPCR regulators in vitro and in vivo [1,2,3,4,5,6,7,8].
What are the synonyms for GO:0045745?
Synonyms include activation of G-protein coupled receptor protein signaling pathway, positive regulation of GPCR protein signaling pathway, and stimulation of G-protein coupled receptor protein signaling pathway.
Which GPCR protects podocytes in diabetic kidney disease?
GPR124 protects podocytes from senescence and injury in diabetic kidney disease.
How does GPR120 inhibit colitis?
GPR120 inhibits colitis through regulation of CD4+ T cell interleukin 10 production.
What is the role of TGR5 in intestinal regeneration?
TGR5 activation by bile acids promotes intestinal stem cell activation and epithelial regeneration.
Conclusion
GO:0045745, positive regulation of G protein-coupled receptor signaling pathway, is a critical biological process that amplifies GPCR-mediated signals essential for physiology and disease. Key genes such as GPR124, ADGRG6, GPR120, GPR91, TGR5, GPR31, and LGR4 have been shown to positively regulate GPCR signaling in diverse contexts, including kidney protection, bone homeostasis, immune regulation, and tissue regeneration [1,2,3,4,5,6,8]. The discovery of GPCR-G protein-beta-arrestin megacomplexes has revealed new mechanisms for positive regulation. Understanding these pathways offers therapeutic opportunities for diseases ranging from diabetic kidney disease to cancer. CRISPR-based models are indispensable for dissecting these mechanisms and validating drug targets. EDITGENE provides comprehensive CRISPR services to accelerate research in this field.
References
- 1. Li Y et al.. 2025. G-protein coupled receptor GPR124 protects against podocyte senescence and injury in diabetic kidney disease.. Kidney Int 107(4):652-665 PMID: 39828038
- 2. Bian F et al.. 2024. The G protein-coupled receptor ADGRG6 maintains mouse growth plate homeostasis through IHH signaling.. J Bone Miner Res 39(11):1644-1658 PMID: 39236220
- 3. Yang W et al.. 2022. GPR120 Inhibits Colitis Through Regulation of CD4(+) T Cell Interleukin 10 Production.. Gastroenterology 162(1):150-165 PMID: 34536451
- 4. Xie L et al.. 2026. Suppressing MASH fibrotic progression by blocking succinate-GPR91 signaling in HSCs.. Hepatology 83(4):888-906 PMID: 40392081
- 5. Sorrentino G et al.. 2020. Bile Acids Signal via TGR5 to Activate Intestinal Stem Cells and Epithelial Regeneration.. Gastroenterology 159(3):956-968.e8 PMID: 32485177
- 6. Jin J et al.. 2025. Pla2g7 regulates bone homeostasis via Alox12/12-HETE/Gpr31 signaling axis.. Nat Commun 16(1):11449 PMID: 41372218
- 7. He G et al.. 2026. A GPCR-G protein-β-arrestin megacomplex enabled by a versatile allosteric modulator.. Cell 189(5):1434-1450.e22 PMID: 41605208
- 8. Yue Z et al.. 2022. RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis.. J Clin Invest 132(2) PMID: 34847079
