GO:0106072 negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway: Signaling Brake, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0106072 describes any process that stops, prevents, or reduces the frequency, rate, or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway.
• The term is a biological_process child of negative regulation of G protein-coupled receptor signaling and is defined by QuickGO as the negative regulation of cAMP-generating GPCR signaling.
• Key molecular brakes include truncated RGS3, which directly suppresses GPCR-stimulated adenylyl cyclase and phospholipase C activity.
• PAC1 receptor (ADCYAP1R1) signaling is a canonical adenylate cyclase-activating GPCR pathway that is subject to negative regulation at the receptor level, including suppression by transglutaminase 2.
• Dysregulation of this negative regulation is linked to neurodevelopmental, circadian, and neurodegenerative phenotypes in mouse models [5,6,7,8].
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to causally test candidate negative regulators of this pathway.
Description
G protein-coupled receptors (GPCRs) that activate adenylate cyclase constitute one of the most widespread signaling systems in eukaryotic cells, converting extracellular signals into intracellular cAMP. The Gene Ontology term GO:0106072, negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, captures the biological processes that attenuate this cAMP-generating cascade. This term is a biological_process and is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of an adenylate cyclase-activating GPCR signaling pathway. Researchers study this term because unrestrained cAMP signaling downstream of GPCRs contributes to endocrine, neuronal, and metabolic phenotypes, and because negative regulators such as RGS proteins provide druggable nodes for pathway tuning. Mechanistically, negative regulation can occur at the receptor, G protein, or effector level. A well-documented example is the truncated form of RGS3, which negatively regulates GPCR stimulation of adenylyl cyclase and phosphoinositide phospholipase C, thereby reducing cAMP accumulation. In the PACAP/PAC1 receptor system, a prototypical adenylate cyclase-activating GPCR axis, negative regulation of receptor expression by transglutaminase 2 activation suppresses PAC1 gene transcription and downstream signaling. These examples illustrate that GO:0106072 encompasses diverse molecular strategies, including receptor desensitization, G protein inactivation, and transcriptional suppression of pathway components [1,2]. Because the term is defined by its regulatory outcome rather than a single molecular mechanism, it is best studied using combinations of genetic perturbation, second-messenger measurement, and transcriptomic readouts. The sections below summarize the definition, core biology, key genes, disease relevance, and experimental methods for interrogating GO:0106072.
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway At A Glance
| GO ID | GO:0106072 |
|---|---|
| GO term | negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway |
| Ontology | biological_process |
| Synonym | negative regulation of adenylate cyclase-activating G-protein coupled receptor signaling pathway |
| Definition | Any process that stops, prevents or reduces the frequency, rate or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway. |
| Major function | Attenuation of cAMP-generating GPCR signaling through receptor, G protein, or effector-level mechanisms. |
| Example regulator | Truncated RGS3 negatively regulates GPCR stimulation of adenylyl cyclase and phospholipase C. |
| Example pathway | PACAP/PAC1 receptor signaling is an adenylate cyclase-activating GPCR axis subject to negative regulation. |
| Disease relevance | Linked to neurodevelopmental, circadian, and neurodegenerative phenotypes in model systems [5,6,7,8]. |
What Is GO:0106072?
GO:0106072 is a Gene Ontology biological_process term meaning any process that stops, prevents, or reduces the frequency, rate, or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway. In practice, this includes mechanisms that dampen cAMP production or downstream cAMP-dependent effects triggered by GPCRs that couple to Gs and activate adenylate cyclase. The synonym negative regulation of adenylate cyclase-activating G-protein coupled receptor signaling pathway is used interchangeably.
Why Is negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Important in Cell Biology?
GO:0106072 matters because cAMP-generating GPCR signaling controls neuronal differentiation, endocrine function, circadian rhythms, and metabolic homeostasis, and its negative regulation determines the amplitude and duration of these responses [2,6,7,8]. Loss of negative regulation can lead to excessive cAMP signaling, whereas excessive negative regulation can blunt physiological responses, making this term central to understanding both normal physiology and disease [1,2].
• Defines the brake on cAMP-generating GPCR pathways that control neuronal proliferation and differentiation [6,7].
• RGS3 truncation directly suppresses GPCR-stimulated adenylyl cyclase, providing a molecular paradigm for the term.
• PAC1 receptor suppression by transglutaminase 2 illustrates transcriptional negative regulation of an adenylate cyclase-activating GPCR.
• Altered PAC1 signaling affects circadian food anticipatory activity rhythms in mice.
• PACAP/PAC1 signaling interacts with Sonic hedgehog to control cerebellar granule precursor proliferation.
• PACAP ligand/receptor system regulates cerebral cortical neurogenesis.
• Dopamine D2 receptor regulation of gonadotropin alpha-subunit gene in gonadotrophs involves GPCR-cAMP crosstalk.
• cAMP-dependent, PKA-independent signaling through Egr1 mediates neuritogenesis, showing pathway complexity.
• Testis degeneration in Alzheimer's disease mouse models may involve altered GPCR-cAMP signaling.
• Provides a conceptual framework for designing CRISPR perturbations that tune GPCR-cAMP output.
What Happens During negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway?
Receptor-level desensitization and transcriptional suppression
In simple terms: The cell reduces the number or activity of the receptor so fewer signals get through.
Negative regulation can begin at the receptor itself. In the PACAP/PAC1 system, activation of transglutaminase 2 suppresses PAC1 gene expression, reducing the abundance of this adenylate cyclase-activating GPCR and thereby limiting downstream cAMP signaling. This transcriptional suppression represents one entry point for GO:0106072, because fewer PAC1 receptors translate into reduced adenylate cyclase activation.
G protein inactivation by RGS proteins
In simple terms: Helper proteins switch off the G protein so it stops activating adenylate cyclase.
Regulators of G protein signaling (RGS) proteins accelerate the inactivation of G alpha subunits. A truncated form of RGS3 has been shown to negatively regulate GPCR stimulation of adenylyl cyclase and phosphoinositide phospholipase C, directly damping cAMP production. This establishes RGS3 as a molecular executor of GO:0106072 at the G protein level.
Effector-level modulation of adenylyl cyclase
In simple terms: The enzyme that makes cAMP can be turned down directly.
Beyond receptor and G protein control, negative regulation can target adenylyl cyclase activity itself. The truncated RGS3 form reduces GPCR-stimulated adenylyl cyclase activity, indicating that effector-level inhibition is part of the term. Such effector modulation changes the frequency and extent of cAMP accumulation without necessarily altering receptor number.
Downstream cAMP-PKA-independent and PKA-dependent outputs
In simple terms: Even when cAMP is made, the cell can change what the signal does.
Negative regulation of the pathway can also be reflected in downstream outputs. A cAMP-dependent, protein kinase A-independent signaling pathway mediates neuritogenesis through Egr1 in PC12 cells, showing that cAMP generated by adenylate cyclase-activating GPCRs can feed into non-canonical effectors. Dopamine D2 receptor expression and regulation of the gonadotropin alpha-subunit gene in clonal gonadotroph LbetaT2 cells further illustrates how GPCR-cAMP signaling is integrated with endocrine gene regulation.
Physiological consequences in neural and circadian systems
In simple terms: Turning the pathway down changes how the brain develops and keeps time.
The PACAP ligand/receptor system regulates cerebral cortical neurogenesis, and PACAP interacts with Sonic hedgehog to control cerebellar granule precursor cell proliferation, so negative regulation of this adenylate cyclase-activating GPCR axis influences neural development [6,7]. In addition, PAC1-deficient mice show altered circadian food anticipatory activity rhythms, linking negative regulation of this pathway to behavioral timing.
Key Genes Involved in GO:0106072 negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
The following genes and proteins are experimentally implicated in negative regulation of adenylate cyclase-activating GPCR signaling or in the canonical PACAP/PAC1 axis that this term regulates.
| Gene | Major Role | Research Relevance |
|---|---|---|
| RGS3 | Truncated form negatively regulates GPCR-stimulated adenylyl cyclase and phospholipase C | Direct molecular executor of GO:0106072 |
| ADCYAP1R1 (PAC1) | Adenylate cyclase-activating GPCR for PACAP; subject to negative regulation | Receptor-level target for suppression studies |
| TGM2 | Transglutaminase 2 activation suppresses PAC1 gene expression | Upstream regulator of receptor-level negative regulation |
| ADCYAP1 (PACAP) | Ligand for PAC1; regulates neurogenesis and proliferation [6,7] | Ligand-receptor axis controlling cAMP [6,7] |
| DRD2 | Dopamine D2 receptor; modulates gonadotropin alpha-subunit gene | GPCR-cAMP crosstalk in endocrine cells |
| EGR1 | Mediates cAMP-dependent, PKA-independent neuritogenesis | Downstream effector of cAMP signaling |
| SHH | Sonic hedgehog interacts with PACAP to control cerebellar precursor proliferation | Developmental crosstalk with GPCR-cAMP pathway |
| GNAS | Gs alpha subunit activating adenylate cyclase downstream of GPCRs | Core G protein node for pathway regulation |
| ADCY1-9 | Adenylate cyclase isoforms generating cAMP | Effector enzymes targeted by negative regulation |
| PRKACA | cAMP-dependent protein kinase A catalytic subunit | Canonical downstream kinase |
| PRKACB | cAMP-dependent protein kinase A catalytic subunit beta | Canonical downstream kinase |
| CREB1 | cAMP response element-binding protein | Transcription factor downstream of cAMP |
| RGS2 | Regulator of G protein signaling family member | Potential G protein brake |
| RGS4 | Regulator of G protein signaling family member | Potential G protein brake |
| RGS10 | Regulator of G protein signaling family member | Potential G protein brake |
| ARRB1 | Beta-arrestin 1; mediates receptor desensitization | Receptor-level negative regulation |
| ARRB2 | Beta-arrestin 2; mediates receptor desensitization | Receptor-level negative regulation |
| GRK2 | G protein-coupled receptor kinase 2 | Phosphorylates activated GPCRs to promote desensitization |
How Is negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Regulated?
Negative regulation of adenylate cyclase-activating GPCR signaling is itself regulated at multiple levels. Transcriptional control is exemplified by transglutaminase 2-mediated suppression of the PAC1 gene, which reduces receptor availability. Post-translational control is exemplified by truncated RGS3, which attenuates GPCR-stimulated adenylyl cyclase activity. Downstream, cAMP can engage PKA-dependent and PKA-independent effectors such as Egr1, which may feed back on pathway output. Endocrine contexts, such as dopamine D2 receptor regulation of the gonadotropin alpha-subunit gene, further show that the pathway is tuned by cell-type-specific inputs.
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ADCYAP1R1 (PAC1) | Circadian rhythm and neurodevelopmental biology | PAC1 knockout mouse |
| TGM2 | PAC1 transcriptional suppression | TGM2 overexpression or knockout cell lines |
| RGS3 | GPCR-cAMP signaling attenuation | RGS3 truncation knock-in cells |
| DRD2 | Endocrine gonadotropin regulation | LbetaT2 gonadotroph cells |
| ADCYAP1 (PACAP) | Cortical neurogenesis and cerebellar proliferation [6,7] | PACAP knockout mouse [6,7] |
Neurodevelopmental and neurodegenerative conditions
PACAP/PAC1 signaling regulates cerebral cortical neurogenesis and cerebellar granule precursor proliferation, so altered negative regulation of this adenylate cyclase-activating GPCR axis may contribute to neurodevelopmental phenotypes [6,7]. In Alzheimer's disease mouse models, testis degeneration has been described, suggesting that GPCR-cAMP-related pathways may be affected in peripheral tissues during neurodegeneration.
Circadian and behavioral disorders
PAC1-deficient mice display altered circadian food anticipatory activity rhythms, indicating that loss of this adenylate cyclase-activating GPCR pathway component disrupts behavioral timing. Negative regulation of PAC1 signaling is therefore relevant to circadian biology.
Endocrine and reproductive dysfunction
Dopamine D2 receptor expression and regulation of the gonadotropin alpha-subunit gene in clonal gonadotroph LbetaT2 cells demonstrate that GPCR-cAMP signaling controls endocrine gene expression. Disrupted negative regulation could therefore impact gonadotropin regulation and reproductive function.
From negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of RGS3 increase GPCR-stimulated cAMP? | RGS3 knockout cell line |
| Does TGM2 activation suppress PAC1 transcription? | TGM2 overexpression or knockout cells |
| Does PAC1 loss alter circadian behavior? | PAC1 knockout mouse |
| Does PACAP loss affect cortical neurogenesis? | PACAP knockout mouse [6,7] |
| Does D2 receptor modulate gonadotropin alpha-subunit? | LbetaT2 gonadotroph cells |
| Does cAMP drive PKA-independent neuritogenesis? | PC12 cells |
How to Study the negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| cAMP assay | Intracellular cAMP levels | GPCR-stimulated adenylate cyclase activity |
| qPCR | mRNA expression of PAC1 or target genes | Transcriptional negative regulation |
| Reporter assay | Promoter activity | PAC1 or gonadotropin alpha-subunit regulation [1,4] |
| Neurite outgrowth assay | Neuronal differentiation | cAMP-dependent neuritogenesis |
| Proliferation assay | Cell proliferation | Cerebellar granule precursor proliferation |
| Behavioral monitoring | Circadian food anticipatory activity | PAC1 knockout phenotyping |
| Western blot | Protein expression and phosphorylation | RGS3 or downstream effector levels |
| Immunohistochemistry | Tissue protein localization | Neurodegeneration models |
cAMP measurement and GPCR signaling assays
Direct measurement of intracellular cAMP is the primary readout for adenylate cyclase-activating GPCR signaling and its negative regulation. Such assays can detect changes caused by RGS3 truncation or PAC1 suppression [1,2].
Transcriptional and gene expression analysis
Quantitative PCR and reporter assays can measure PAC1 gene suppression by transglutaminase 2 or gonadotropin alpha-subunit regulation by dopamine D2 receptor signaling [1,4].
Neuronal differentiation and proliferation assays
PC12 neuritogenesis and cerebellar granule precursor proliferation assays are used to study downstream consequences of cAMP signaling and its negative regulation [3,6].
Behavioral circadian phenotyping
Food anticipatory activity rhythms in PAC1-deficient mice provide an in vivo readout for altered adenylate cyclase-activating GPCR signaling.
How CRISPR Can Be Used to Study GO:0106072 negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
Knockout
CRISPR knockout of candidate negative regulators such as RGS3 can test whether loss of the brake increases GPCR-stimulated cAMP production. Knockout of PAC1 or PACAP can model loss of the adenylate cyclase-activating GPCR axis itself [6,7,8].
Point Mutation
Point mutations can be introduced into RGS3 or PAC1 to dissect domain-specific functions, such as the truncation that confers negative regulation on adenylyl cyclase.
Knock-in
Knock-in of tagged or reporter alleles at the PAC1 locus enables tracking of receptor expression under conditions of negative regulation, such as transglutaminase 2 activation.
Overexpression
Overexpression of truncated RGS3 or transglutaminase 2 can be used to enhance negative regulation and measure suppression of GPCR-stimulated adenylyl cyclase or PAC1 transcription [1,2].
How EDITGENE Supports negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Research
Researchers studying negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in dampening cAMP signaling or is merely correlated with pathway output. EDITGENE provides CRISPR-based cell models and screening services to establish causality.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway research.
Frequently Asked Questions About negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
What is GO:0106072?
GO:0106072 is the Gene Ontology biological_process term for negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, meaning any process that stops, prevents, or reduces this cAMP-generating GPCR pathway.
What genes are involved in negative regulation of adenylate cyclase-activating GPCR signaling?
Key genes include RGS3, which negatively regulates GPCR-stimulated adenylyl cyclase, and TGM2, which suppresses PAC1 receptor gene expression [1,2].
How does RGS3 negatively regulate adenylyl cyclase?
A truncated form of RGS3 negatively regulates GPCR stimulation of adenylyl cyclase and phosphoinositide phospholipase C, reducing cAMP production.
What is the PAC1 receptor?
PAC1 (ADCYAP1R1) is an adenylate cyclase-activating GPCR for PACAP that is subject to negative regulation, including transcriptional suppression by transglutaminase 2.
Why is negative regulation of GPCR-cAMP signaling important?
It controls the amplitude and duration of cAMP signals that regulate neurogenesis, circadian rhythms, and endocrine gene expression [4,6,7,8].
What diseases are linked to this pathway?
Altered PACAP/PAC1 signaling is linked to circadian rhythm changes, neurodevelopmental processes, and peripheral phenotypes in Alzheimer's disease mouse models [5,8].
How can I study GO:0106072 in the lab?
Use cAMP assays, qPCR for PAC1, neurite outgrowth assays, and behavioral circadian monitoring in knockout models [1,2,3,8].
What CRISPR models are useful for this pathway?
Knockout of RGS3 or PAC1, point mutations in RGS3, knock-in reporters at PAC1, and overexpression of TGM2 are all useful [1,2,8].
Does PACAP regulate neurogenesis?
Yes, the PACAP ligand/receptor system regulates cerebral cortical neurogenesis and interacts with Sonic hedgehog in cerebellar granule precursor proliferation [6,7].
What is the role of dopamine D2 receptor in this pathway?
Dopamine D2 receptor expression and regulation of the gonadotropin alpha-subunit gene in gonadotroph cells show GPCR-cAMP crosstalk in endocrine regulation.
Conclusion
GO:0106072 provides a precise ontology framework for studying how cells dampen cAMP-generating GPCR signaling. Experimental evidence implicates receptor-level suppression, RGS-mediated G protein inactivation, and downstream effector modulation in this process [1,2]. Because these mechanisms influence neurogenesis, circadian behavior, and endocrine function, they are relevant to a broad range of physiological and disease contexts [4,6,7,8]. CRISPR-based knockout, point-mutation, knock-in, and overexpression models offer causal tests of candidate regulators within this term.
References
- 1. Miura A et al.. 2013. Pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) gene is suppressed by transglutaminase 2 activation.. J Biol Chem 288(45):32720-32730 PMID: 24045949
- 2. Chatterjee TK et al.. 1997. A truncated form of RGS3 negatively regulates G protein-coupled receptor stimulation of adenylyl cyclase and phosphoinositide phospholipase C.. J Biol Chem 272(24):15481-7 PMID: 9182581
- 3. Ravni A et al.. 2008. A cAMP-dependent, protein kinase A-independent signaling pathway mediating neuritogenesis through Egr1 in PC12 cells.. Mol Pharmacol 73(6):1688-708 PMID: 18362103
- 4. Mutiara S et al.. 2006. Dopamine D(2) receptor expression and regulation of gonadotropin alpha-subunit gene in clonal gonadotroph LbetaT2 cells.. Mol Cell Endocrinol 259(1-2):22-9 PMID: 16959402
- 5. Szegeczki V et al.. 2020. Alzheimer's Disease Mouse as a Model of Testis Degeneration.. Int J Mol Sci 21(16) PMID: 32785075
- 6. Nicot A et al.. 2002. Pituitary adenylate cyclase-activating polypeptide and sonic hedgehog interact to control cerebellar granule precursor cell proliferation.. J Neurosci 22(21):9244-54 PMID: 12417650
- 7. Dicicco-Bloom E et al.. 1998. The PACAP ligand/receptor system regulates cerebral cortical neurogenesis.. Ann N Y Acad Sci 865:274-89 PMID: 9928022
- 8. Hannibal J et al.. 2016. Altered Circadian Food Anticipatory Activity Rhythms in PACAP Receptor 1 (PAC1) Deficient Mice.. PLoS One 11(1):e0146981 PMID: 26757053
