GO:0141162 negative regulation of cAMP/PKA signal transduction: Signaling Brake, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0141162 describes any process that stops, prevents, or reduces the frequency, rate, or extent of cAMP/PKA signal transduction.
• cAMP/PKA signaling is a ubiquitous second-messenger pathway, and its negative regulation is essential for terminating or dampening responses in immune, neuronal, cardiac, and metabolic cells [2,6].
• Key negative regulators include phosphodiesterases (PDEs), A-kinase anchoring proteins (AKAPs), protein phosphatases, and GPCR desensitization machinery [1,7].
• Dysregulation of this brake contributes to diseases such as cardiac hypertrophy, glioblastoma progression, T-cell dysfunction, and TDP-43 proteinopathies [1,6,8].
• CRISPR knockout, point mutation, knock-in, and overexpression models enable precise interrogation of negative regulators in disease-relevant cell types [3,5].
• EDITGENE provides end-to-end CRISPR cell model and library screening services to dissect GO:0141162 mechanisms at scale.
Description
The Gene Ontology term GO:0141162, negative regulation of cAMP/PKA signal transduction, captures the cellular processes that stop, prevent, or reduce the frequency, rate, or extent of signaling through cyclic AMP (cAMP) and protein kinase A (PKA). This term is a biological_process and is synonymous with negative regulation of cAMP/PKA signaling. cAMP/PKA signaling is one of the most widespread second-messenger pathways in eukaryotes, controlling metabolism, gene expression, cell growth, immune activation, and neuronal function [2,6]. Because unrestrained cAMP/PKA activity can drive pathological outcomes, cells deploy multiple layers of negative regulation, including phosphodiesterase-mediated cAMP degradation, phosphatase-mediated PKA inactivation, and anchoring proteins that localize and restrain PKA [1,7]. For researchers, GO:0141162 provides a conceptual framework to study how cells terminate or dampen cAMP/PKA signals. Experimental evidence shows that negative regulation of this pathway is critical in T-cell receptor activation, where the cAMP-PKA-Csk axis suppresses signaling in lipid rafts. In the heart, A2AR-D2R dimerization and PDE10A-mediated control of cAMP/PKA signaling modulate cardiac hypertrophy. In neurons, cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization, and its negative regulation may protect against proteinopathy. Thus, understanding GO:0141162 is essential for dissecting disease mechanisms and identifying therapeutic targets. This article integrates the QuickGO definition with verified PubMed literature to provide a research-grade overview of the genes, mechanisms, disease links, and CRISPR-based methods used to study negative regulation of cAMP/PKA signal transduction.
negative regulation of cAMP/PKA signal transduction At A Glance
| GO ID | GO:0141162 |
|---|---|
| GO term | negative regulation of cAMP/PKA signal transduction |
| Ontology | biological_process |
| Synonym | negative regulation of cAMP/PKA signaling |
| Major function | Terminates or dampens cAMP-dependent PKA signaling to prevent excessive or prolonged pathway activation. |
| Key molecular players | Phosphodiesterases (PDEs), A-kinase anchoring proteins (AKAPs), protein phosphatases, GPCR kinases and arrestins [1,7]. |
| Cellular contexts | Immune cells, cardiomyocytes, neurons, adipocytes, and cancer cells [1,2,6,7,8]. |
| Disease relevance | Cardiac hypertrophy, glioblastoma, T-cell dysfunction, TDP-43 proteinopathy, and bone loss [1,3,6,8]. |
| Research methods | CRISPR KO/point mutation/knock-in/overexpression, phospho-PKA substrates, cAMP sensors, and phenotypic assays [3,5]. |
What Is GO:0141162?
GO:0141162 is defined by QuickGO as any process that stops, prevents, or reduces the frequency, rate, or extent of cAMP/PKA signal transduction. In practical terms, it encompasses molecular events that lower cAMP levels, inhibit PKA catalytic activity, or uncouple upstream receptors from downstream effectors, thereby acting as a brake on the pathway.
Why Is negative regulation of cAMP/PKA signal transduction Important in Cell Biology?
Negative regulation of cAMP/PKA signal transduction is essential for maintaining cellular homeostasis and preventing pathological overactivation of one of the most pleiotropic signaling pathways. Its dysfunction is implicated in cardiovascular disease, cancer, immune disorders, and neurodegeneration, making it a high-value area for therapeutic intervention and biomarker discovery [1,2,6,8].
• Prevents excessive cardiac hypertrophy by restraining cAMP/PKA signaling in cardiomyocytes.
• Suppresses T-cell receptor activation through the cAMP-PKA-Csk pathway in lipid rafts.
• Limits osteoclastogenesis and bone loss via adhesion GPCR ADGRD1/GPR133 signaling.
• Modulates TDP-43 aggregation and mislocalization, linking cAMP/PKA regulation to neurodegeneration.
• Controls adipocyte function through A-kinase-anchoring proteins such as MEDAG.
• Restrains glioblastoma cell migration and invasion via MOB2 regulation of FAK/Akt and cAMP/PKA.
• Influences NK cell cytotoxicity and immunotherapy responses through dopamine signaling.
• Provides a mechanistic basis for phosphodiesterase inhibitor and GPCR-targeted drug development.
• Serves as a model for two-component signal transduction intersections in lower eukaryotes.
• Enables CRISPR-based functional genomics to identify novel negative regulators [3,5].
What Happens During negative regulation of cAMP/PKA signal transduction?
Receptor desensitization and uncoupling
In simple terms: The cell first turns down the signal at the receptor level so less cAMP is made.
Negative regulation often begins with GPCR desensitization, where activated receptors are phosphorylated by GPCR kinases and bound by arrestins, preventing further Gs-mediated activation of adenylyl cyclase. This reduces cAMP production and thus dampens PKA signaling. In T cells, the cAMP-PKA-Csk pathway operates in lipid rafts to negatively regulate T-cell receptor activation, illustrating receptor-proximal control.
cAMP degradation by phosphodiesterases
In simple terms: Enzymes called phosphodiesterases chew up cAMP so it cannot keep PKA active.
Phosphodiesterases (PDEs) hydrolyze cAMP to AMP, directly lowering the second-messenger pool available to activate PKA. PDE10A-mediated regulation of cAMP/PKA signaling in cardiac hypertrophy demonstrates how PDE activity can negatively regulate the pathway. This step is a major node for pharmacological intervention.
PKA inactivation by phosphatases and inhibitory subunits
In simple terms: Even if PKA is turned on, phosphatases and inhibitory proteins can switch it off.
Protein phosphatases remove phosphate groups from PKA substrates, reversing phosphorylation events. Additionally, endogenous PKA inhibitors and regulatory subunit sequestration can limit catalytic activity. In adipocytes, MEDAG functions as an A-kinase-anchoring protein, localizing PKA and modulating its output, which can contribute to negative regulation.
Anchoring and spatial restriction of PKA
In simple terms: Scaffolding proteins keep PKA in the right place, preventing it from signaling everywhere.
A-kinase anchoring proteins (AKAPs) tether PKA to specific subcellular compartments, ensuring that phosphorylation is confined to appropriate substrates. This spatial restriction can act as a negative regulatory mechanism by preventing inappropriate signaling. MEDAG has been identified as an AKAP in adipocytes, highlighting the role of anchoring in pathway control.
Cross-talk with other signaling pathways
In simple terms: Other pathways can put the brakes on cAMP/PKA by interfering with its components.
Negative regulation of cAMP/PKA signaling intersects with other cascades. For example, MOB2 suppresses glioblastoma cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling, indicating cross-talk between adhesion and cAMP pathways. In Dictyostelium, the cAMP/PKA and two-component signal transduction systems intersect, showing evolutionary conservation of negative regulatory mechanisms.
Key Genes Involved in GO:0141162 negative regulation of cAMP/PKA signal transduction
The following genes and proteins are experimentally implicated in negative regulation of cAMP/PKA signal transduction, based on verified PubMed literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PDE10A | Hydrolyzes cAMP, reducing PKA activation | Cardiac hypertrophy model; target for PDE inhibitors |
| DRD2 | Dopamine receptor that modulates cAMP/PKA via Gi signaling | A2AR-D2R dimerization in cardiac hypertrophy |
| ADORA2A | Adenosine receptor that can couple to Gs or Gi depending on context | Dimerization with D2R affects PDE10A-mediated signaling |
| CSK | C-terminal Src kinase, negatively regulates T-cell receptor via cAMP-PKA | T-cell lipid raft signaling |
| PRKACA | Catalytic subunit of PKA; target of negative regulation | Central to cAMP/PKA pathway |
| ADGRD1 (GPR133) | Adhesion GPCR that negatively regulates osteoclastogenesis | Bone loss protection via cAMP/PKA modulation |
| MEDAG | A-kinase-anchoring protein in adipocytes | Localizes PKA and modulates adipocyte signaling |
| MOB2 | Regulates FAK/Akt and cAMP/PKA signaling | Suppresses glioblastoma migration and invasion |
| TDP-43 | RNA-binding protein; aggregation regulated by cAMP/PKA | Neurodegeneration model |
| PDE4 family | cAMP-specific phosphodiesterases | Broad negative regulators of cAMP/PKA |
| PRKAR1A | Regulatory subunit of PKA | Controls PKA activity and localization |
| PRKAR2A | Regulatory subunit of PKA | Anchors PKA to AKAPs |
| AKAP family | Scaffold proteins that anchor PKA | Spatial regulation of cAMP/PKA |
| PPP1CA | Protein phosphatase 1 catalytic subunit | Dephosphorylates PKA substrates |
| PPP2CA | Protein phosphatase 2A catalytic subunit | Negative regulation of PKA targets |
| ARRB1 | Beta-arrestin 1, desensitizes GPCRs | Reduces cAMP production |
| ARRB2 | Beta-arrestin 2, desensitizes GPCRs | Reduces cAMP production |
| GRK2 | GPCR kinase 2, phosphorylates activated receptors | Promotes desensitization |
How Is negative regulation of cAMP/PKA signal transduction Regulated?
Negative regulation of cAMP/PKA signal transduction is itself regulated at multiple levels. Phosphodiesterase expression and activity are controlled by hormones, neurotransmitters, and inflammatory signals. AKAPs such as MEDAG localize PKA and can be regulated by metabolic cues in adipocytes. Cross-talk with FAK/Akt signaling via MOB2 modulates cAMP/PKA output in glioblastoma. In T cells, the cAMP-PKA-Csk axis is integrated with T-cell receptor activation in lipid rafts. These layers ensure that the brake on cAMP/PKA signaling is context-dependent and dynamic.
negative regulation of cAMP/PKA signal transduction and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| PDE10A | Cardiac hypertrophy | Cardiomyocyte-specific knockout or overexpression |
| MOB2 | Glioblastoma migration and invasion | Glioblastoma cell lines with MOB2 knockout |
| TDP-43 | ALS/FTD proteinopathy | Neuronal cells expressing mutant TDP-43 |
| ADGRD1 | Bone loss / osteoclastogenesis | Osteoclast precursors with ADGRD1 activation |
| CSK | T-cell dysfunction | Jurkat or primary T cells with CSK knockout |
Cardiac hypertrophy and heart failure
PDE10A-mediated regulation of cAMP/PKA signaling is implicated in cardiac hypertrophy. A2AR-D2R dimerization and D2R-biased signaling influence PDE10A activity, and disruption of this negative regulation can exacerbate hypertrophic responses. Targeting this axis may offer therapeutic opportunities for heart failure.
Cancer progression and metastasis
MOB2 suppresses glioblastoma cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling, indicating that loss of negative regulation can promote tumor aggressiveness. Additionally, sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling, which may involve cAMP/PKA modulation and synergize with immunotherapy in triple-negative breast cancer.
Neurodegeneration and TDP-43 proteinopathy
cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization, and negative regulation of this pathway may protect against TDP-43 proteinopathies such as amyotrophic lateral sclerosis and frontotemporal dementia. Modulating cAMP/PKA activity could be a therapeutic strategy.
Immune dysfunction and bone loss
The cAMP-PKA-Csk pathway negatively regulates T-cell receptor activation, and its dysregulation can lead to immune disorders. In bone, exogenous activation of ADGRD1/GPR133 protects against bone loss by negatively regulating osteoclastogenesis, highlighting the role of cAMP/PKA negative regulation in skeletal health.
From negative regulation of cAMP/PKA signal transduction-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of PDE10A enhance cAMP/PKA signaling and hypertrophy? | PDE10A knockout cardiomyocytes |
| Does MOB2 negatively regulate cAMP/PKA in glioblastoma? | MOB2 knockout glioblastoma cells |
| Does ADGRD1 activation suppress osteoclastogenesis via cAMP/PKA? | ADGRD1 overexpression in osteoclast precursors |
| Does mutant TDP-43 alter cAMP/PKA negative regulation? | TDP-43 knock-in neurons |
| Does MEDAG anchor PKA and modulate adipocyte signaling? | MEDAG knockout adipocytes |
| Does CSK mediate cAMP-PKA negative regulation in T cells? | CSK knockout T cells |
How to Study the negative regulation of cAMP/PKA signal transduction Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Phospho-PKA substrate Western blot | Phosphorylation of PKA targets | Assessing pathway activity in KO cells |
| cAMP biosensor imaging | Intracellular cAMP dynamics | Real-time monitoring in live cells |
| CRISPR knockout screening | Gene requirement for negative regulation | Identifying novel regulators [3,5] |
| RNA-seq | Transcriptional changes upon pathway modulation | Downstream target discovery |
| Co-immunoprecipitation | Protein-protein interactions (e.g., AKAP-PKA) | Mapping regulatory complexes |
| Phosphoproteomics | Global phosphorylation changes | Unbiased pathway profiling |
| Migration/invasion assays | Cell motility | Glioblastoma studies |
| Osteoclast differentiation assays | Osteoclastogenesis | Bone biology |
Phospho-PKA substrate profiling
Western blotting with phospho-PKA substrate antibodies measures the phosphorylation status of PKA targets, providing a readout of negative regulation. This method is widely used in cardiomyocyte and neuronal models [1,6].
cAMP measurement with biosensors
Genetically encoded cAMP sensors (e.g., EPAC-based) allow real-time monitoring of cAMP levels in live cells. This is critical for assessing phosphodiesterase activity and receptor desensitization.
CRISPR-based functional genomics
Pooled CRISPR knockout or activation screens can identify novel negative regulators of cAMP/PKA signaling. Libraries targeting kinases, phosphatases, and GPCRs are particularly useful [3,5].
Proteomics and interactomics
Affinity purification mass spectrometry can map AKAP-PKA interactions and identify dynamic changes in the negative regulation complex. This approach has been used to study MEDAG in adipocytes.
How CRISPR Can Be Used to Study GO:0141162 negative regulation of cAMP/PKA signal transduction
Knockout
CRISPR knockout of negative regulators such as PDE10A, MOB2, or CSK can reveal their role in dampening cAMP/PKA signaling. For example, MOB2 knockout in glioblastoma cells increases migration and invasion, confirming its negative regulatory function. EDITGENE provides custom knockout cell lines for these targets.
Point Mutation
Point mutations can mimic disease-associated variants or disrupt catalytic activity. For instance, mutating the catalytic domain of PDE10A can abolish its cAMP-hydrolyzing activity, leading to enhanced PKA signaling. EDITGENE offers precision point mutation models.
Knock-in
Knock-in of tagged or reporter alleles allows real-time tracking of negative regulators. Tagging MEDAG with a fluorescent protein enables visualization of its localization in adipocytes. EDITGENE provides knock-in services for endogenous tagging.
Overexpression
Overexpression of negative regulators such as ADGRD1 or MEDAG can suppress cAMP/PKA signaling and protect against pathological outcomes. For example, ADGRD1 overexpression protects against bone loss by negatively regulating osteoclastogenesis. EDITGENE offers stable overexpression cell lines.
How EDITGENE Supports negative regulation of cAMP/PKA signal transduction Research
Researchers studying negative regulation of cAMP/PKA signal transduction-related genes often need to determine whether a candidate gene is causally involved in dampening the pathway. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this discovery.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cAMP/PKA signal transduction research.
Frequently Asked Questions About negative regulation of cAMP/PKA signal transduction
What is GO:0141162?
GO:0141162 is the Gene Ontology term for negative regulation of cAMP/PKA signal transduction, describing any process that stops, prevents, or reduces the frequency, rate, or extent of cAMP/PKA signaling.
What genes are involved in negative regulation of cAMP/PKA signal transduction?
Key genes include PDE10A, MOB2, CSK, ADGRD1, MEDAG, and various AKAPs and phosphatases [1,2,3,7,8].
How does cAMP/PKA signaling get turned off?
It is turned off by phosphodiesterases that degrade cAMP, phosphatases that reverse PKA phosphorylation, and receptor desensitization mechanisms [1,2].
Why is negative regulation of cAMP/PKA important in heart disease?
PDE10A-mediated negative regulation prevents excessive cardiac hypertrophy; its dysfunction can lead to heart failure.
What is the role of MOB2 in cAMP/PKA signaling?
MOB2 suppresses glioblastoma cell migration and invasion by regulating FAK/Akt and cAMP/PKA signaling.
How does ADGRD1 negatively regulate osteoclastogenesis?
Exogenous activation of ADGRD1/GPR133 protects against bone loss by negatively regulating osteoclastogenesis, likely via cAMP/PKA modulation.
Can CRISPR be used to study negative regulation of cAMP/PKA?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to dissect this pathway [3,5].
What diseases are linked to dysregulated cAMP/PKA negative regulation?
Cardiac hypertrophy, glioblastoma, T-cell dysfunction, TDP-43 proteinopathy, and bone loss [1,2,3,6,8].
What methods measure cAMP/PKA negative regulation?
Phospho-PKA substrate Western blot, cAMP biosensors, phosphoproteomics, and CRISPR screens [1,6,8].
How does MEDAG function in adipocytes?
MEDAG acts as an A-kinase-anchoring protein, localizing PKA and modulating its signaling output.
Conclusion
GO:0141162, negative regulation of cAMP/PKA signal transduction, is a critical biological process that prevents excessive signaling through one of the most important second-messenger pathways. Its dysregulation contributes to cardiac, immune, neurological, and oncological diseases [1,2,6,8]. CRISPR-based models and functional genomics are powerful tools to uncover new mechanisms and therapeutic targets. EDITGENE offers comprehensive services to support this research.
References
- 1. Chen S et al.. 2025. Role of A(2A)R-D2R Dimerization and D(2)R-Biased Signaling in PDE10A-Mediated Cardiac Hypertrophy.. Circulation 152(19):1371-1392 PMID: 40970278
- 2. Tasken K et al.. 2006. Negative regulation of T-cell receptor activation by the cAMP-PKA-Csk signalling pathway in T-cell lipid rafts.. Front Biosci 11:2929-39 PMID: 16720365
- 3. He L et al.. 2025. Exogenous activation of the adhesion GPCR ADGRD1/GPR133 protects against bone loss by negatively regulating osteoclastogenesis.. Sci Adv 11(28):eads3829 PMID: 40644539
- 4. Thomason PA et al.. 1998. An intersection of the cAMP/PKA and two-component signal transduction systems in Dictyostelium.. EMBO J 17(10):2838-45 PMID: 9582277
- 5. Li G et al.. 2025. Sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling and synergizes immunotherapy in triple-negative breast cancer.. Drug Resist Updat 79:101212 PMID: 39951881
- 6. Ho DM et al.. 2024. cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.. Proc Natl Acad Sci U S A 121(24):e2400732121 PMID: 38838021
- 7. Long F et al.. 2026. MEDAG functions as an A-kinase-anchoring protein in adipocytes.. Mol Cell 86(5):937-953.e9 PMID: 41747731
- 8. Jiang K et al.. 2020. MOB2 suppresses GBM cell migration and invasion via regulation of FAK/Akt and cAMP/PKA signaling.. Cell Death Dis 11(4):230 PMID: 32286266
