GO:0106070 regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0106070 describes any process that modulates the frequency, rate or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway, a central cAMP-generating route in eukaryotic cells.
• The pathway is activated when ligands such as VIP and PACAP bind class B GPCRs, including PAC1, VPAC1 and VPAC2, which couple to Gs and stimulate adenylate cyclase.
• Regulation occurs at multiple levels: ligand availability, receptor trafficking and endosomal signaling, G protein switching, phosphodiesterase activity and downstream kinase feedback.
• PACAP and VIP signaling controls neuronal excitability, stress responses, energy homeostasis, reproduction and cartilage biology, making this GO term relevant to neurobiology, endocrinology and musculoskeletal research.
• Dysregulation of this pathway is implicated in stress-related disorders, metabolic disease, reproductive dysfunction and cancer biology, supporting its use as a therapeutic target.
• CRISPR knockout, point-mutation, knock-in and overexpression models enable causal dissection of receptor, G protein and effector contributions to this regulatory process.
Description
GO:0106070, regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, is a biological process ontology term that captures any mechanism controlling the frequency, rate or extent of a GPCR pathway that activates adenylate cyclase. This pathway is one of the principal routes by which extracellular signals are converted into intracellular cAMP, and its regulation determines whether cells mount sustained, transient or spatially restricted responses. The term is therefore central to understanding how hormones, neuropeptides and neurotransmitters fine-tune cellular physiology. Ligands such as vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) act through class B GPCRs to trigger this cascade, and their functions have been dissected using molecular and genetic approaches. Because the same core pathway operates in neurons, endocrine cells, immune cells and cartilage, its regulation is studied across many organ systems. Researchers annotate genes to GO:0106070 when they experimentally show that a gene product changes the amplitude, duration or location of adenylate cyclase-activating GPCR signaling. This makes the term a practical hub for integrating receptor pharmacology, G protein biology and second-messenger dynamics. Understanding its regulation is also clinically relevant, since altered cAMP signaling contributes to stress-related pathology, metabolic imbalance and cancer.
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway At A Glance
| GO ID | GO:0106070 |
|---|---|
| GO term | regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway |
| Ontology | biological_process |
| Synonym | regulation of adenylate cyclase-activating G-protein coupled receptor signaling pathway |
| Major function | Modulates the frequency, rate or extent of GPCR signaling that activates adenylate cyclase and raises cAMP |
| Representative ligands | VIP and PACAP |
| Representative receptors | PAC1, VPAC1 and VPAC2 |
| Key second messenger | cAMP produced by adenylate cyclase |
| Regulatory layers | Ligand availability, receptor trafficking and endosomal signaling, G protein coupling, phosphodiesterase activity and kinase feedback |
What Is GO:0106070?
In plain terms, GO:0106070 describes the set of processes that adjust how strongly, how long or where an adenylate cyclase-activating GPCR signal occurs. The QuickGO definition states that it is any process that modulates the frequency, rate or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway. It is a biological process term, and its synonym is regulation of adenylate cyclase-activating G-protein coupled receptor signaling pathway. It does not describe the signaling pathway itself, but the regulatory inputs that tune it, including changes in ligand availability, receptor number or localization, G protein coupling, adenylate cyclase activity and cAMP degradation.
Why Is regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Important in Cell Biology?
GO:0106070 matters because adenylate cyclase-activating GPCR signaling is a master regulator of neuronal excitability, endocrine output, energy balance and tissue homeostasis, and its dysregulation is linked to stress-related disorders, metabolic disease and cancer. Defining the regulatory inputs that shape this pathway allows researchers to predict how cells will respond to hormones and neuropeptides, and it provides a framework for therapeutic targeting of receptors, G proteins and downstream effectors.
• Controls cAMP amplitude and duration, which determines cellular responses to VIP and PACAP.
• Regulates neuronal excitability and stress responses through PAC1 receptor signaling, including endosomal pathways.
• Participates in energy homeostasis via hypothalamic PACAP receptor activation.
• Influences mammalian reproductive function through PACAP-dependent regulation.
• Modulates astrocytic glutamate release via system xc-, linking the pathway to neurotransmission.
• Contributes to articular cartilage biology and joint disease mechanisms.
• Is implicated in stress, learning and pathology, making it relevant to neuropsychiatric research.
• Provides a target-rich axis for pharmacological and CRISPR-based interrogation of disease mechanisms.
What Happens During regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway?
Ligand availability and receptor engagement
In simple terms: The signal starts when a messenger molecule reaches its receptor on the cell surface.
Regulation begins with the availability of ligands such as VIP and PACAP, which bind class B GPCRs including PAC1, VPAC1 and VPAC2. Changes in ligand synthesis, release or degradation therefore alter the frequency and extent of pathway activation. Genetic and molecular studies have shown that VIP and PACAP have distinct physiological roles, and their receptor engagement is a primary control point for adenylate cyclase activation.
G protein coupling and adenylate cyclase activation
In simple terms: Once the receptor is active, it switches on a G protein that turns on the enzyme making cAMP.
Activated receptors promote Gs-mediated stimulation of adenylate cyclase, which converts ATP to cAMP. Signal transduction by VIP and PACAP receptors has been reviewed in detail, showing that receptor coupling to G proteins is a regulated step that determines downstream cAMP output. The pathway can also be modulated by receptor desensitization and by switching between G protein partners, which changes the rate and extent of adenylate cyclase activation.
Endosomal signaling and spatial regulation
In simple terms: The signal does not stop at the cell surface; it can continue from inside the cell in small vesicles.
PAC1 receptor signaling can persist from endosomes, where it regulates neuronal excitability and stress responses. This endosomal phase is a distinct regulatory layer because it controls the duration and location of cAMP production, and it can engage unique signaling pathways such as those involved in energy homeostasis. Spatial regulation therefore expands the meaning of GO:0106070 beyond simple on-off control at the plasma membrane.
Downstream feedback and termination
In simple terms: The cell uses brakes, including enzymes that destroy cAMP and kinases that dampen the receptor.
Phosphodiesterases degrade cAMP, while kinases and arrestins can desensitize receptors, providing negative feedback that sets the frequency and extent of signaling. Reviews of VIP and PACAP receptor signal transduction describe these termination mechanisms as integral to pathway regulation. In neurons and astrocytes, such feedback shapes glutamate release and excitability, linking the regulatory process to network-level physiology.
Integration with cellular state
In simple terms: The same signal can do different things depending on what else the cell is doing.
The functional heterogeneity of PACAP illustrates that pathway regulation is context dependent, with stress, learning and pathology altering the outcome of receptor activation. In articular cartilage, PACAP signaling is influenced by the tissue environment, showing that regulation of this pathway is integrated with cell-type-specific programs. This integration is why GO:0106070 is annotated as a regulatory process rather than a fixed linear cascade.
Key Genes Involved in GO:0106070 regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
The genes and proteins most directly associated with GO:0106070 include the ligands VIP and PACAP, their class B GPCRs, G protein subunits and downstream effectors that shape cAMP signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ADCYAP1 | Encodes PACAP, a ligand that activates adenylate cyclase-activating GPCRs | Central to stress, neuronal and endocrine studies |
| VIP | Encodes vasoactive intestinal peptide, a ligand for VPAC receptors | Implicated in physiology and disease across multiple systems |
| ADCYAP1R1 | Encodes the PAC1 receptor | Key receptor for PACAP signaling and endosomal regulation |
| VIPR1 | Encodes VPAC1 receptor | Mediates VIP and PACAP signal transduction |
| VIPR2 | Encodes VPAC2 receptor | Mediates VIP and PACAP signal transduction |
| GNAS | Encodes the Gs alpha subunit that stimulates adenylate cyclase | Core transducer of adenylate cyclase-activating GPCR signaling |
| ADCY1 | Encodes an adenylate cyclase isoform | Produces cAMP downstream of Gs-coupled receptors |
| ADCY2 | Encodes an adenylate cyclase isoform | Contributes to cAMP generation in neurons |
| ADCYAP1R1 variants | Alter receptor function or expression | Studied in stress-related and metabolic phenotypes |
| SLC7A11 | Encodes system xc- component linked to PACAP-regulated glutamate release | Connects pathway regulation to astrocytic glutamate handling |
| PRKACA | Encodes a cAMP-dependent protein kinase catalytic subunit | Mediates downstream phosphorylation and feedback |
| PRKACB | Encodes a cAMP-dependent protein kinase catalytic subunit | Mediates downstream phosphorylation and feedback |
| PDE4 family | Phosphodiesterases that degrade cAMP | Set the duration and amplitude of signaling |
| ARRB1 | Beta-arrestin 1 involved in receptor desensitization | Regulates receptor trafficking and signaling duration |
| ARRB2 | Beta-arrestin 2 involved in receptor desensitization | Regulates receptor trafficking and signaling duration |
| GNAI1 | Gi alpha subunit that can inhibit adenylate cyclase | Provides opposing regulation of cAMP levels |
| CREB1 | Transcription factor activated by cAMP signaling | Reads out pathway activity and drives gene expression |
How Is regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Regulated?
Regulation of GO:0106070 occurs through ligand synthesis and release, receptor expression and trafficking, G protein coupling preferences, phosphodiesterase-mediated cAMP degradation and kinase or arrestin feedback. Endosomal signaling by the PAC1 receptor adds a spatial dimension, allowing cAMP production to continue after internalization and to engage distinct downstream pathways. In the hypothalamus, PACAP receptor activation recruits unique signaling routes that contribute to energy homeostasis, showing that regulation is tissue specific. Functional heterogeneity of PACAP further indicates that stress, learning and pathological states can reshape how this pathway is regulated.
regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ADCYAP1R1 | Stress-related disorders and neuronal excitability | PAC1 knockout and point-mutation neuronal cell lines |
| ADCYAP1 | Stress, learning and pathology | PACAP overexpression and knockout models |
| VIP | Physiology and disease across multiple systems | VIP knockout and knock-in reporter models |
| ADCYAP1R1 | Energy homeostasis and metabolic regulation | Hypothalamic cell models with receptor knockout |
| VIPR1 / VIPR2 | Signal transduction in endocrine and immune cells | VPAC receptor knockout and overexpression lines |
Stress-related and neuropsychiatric disorders
PACAP and its receptor PAC1 are strongly implicated in stress responses, learning and pathology, and altered regulation of adenylate cyclase-activating GPCR signaling may contribute to maladaptive stress phenotypes. Endosomal PAC1 signaling influences neuronal excitability and stress responses, providing a mechanistic link between pathway regulation and neuropsychiatric disease.
Metabolic and energy homeostasis disorders
Hypothalamic PACAP receptor activation recruits signaling pathways involved in energy homeostasis, so dysregulation of this GO process may contribute to metabolic imbalance. Because cAMP signaling is a central integrator of hormonal cues, changes in its regulation can affect feeding and energy expenditure.
Reproductive dysfunction
PACAP is a regulator of mammalian reproductive function, and altered regulation of its signaling pathway has been linked to reproductive physiology and pathology. This makes GO:0106070 relevant to endocrine and fertility research.
Cartilage and musculoskeletal disease
PACAP signaling is present in articular cartilage, where it may influence chondrocyte biology and joint disease. Regulation of adenylate cyclase-activating GPCR signaling in cartilage is therefore an emerging area for musculoskeletal research.
From regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of PAC1 receptor alter cAMP responses? | PAC1 knockout cell line |
| Does a disease-associated variant change receptor coupling? | Point-mutation knock-in of ADCYAP1R1 |
| Where is the receptor localized during signaling? | Tagged knock-in of PAC1 with fluorescent tag |
| Does overexpression of PACAP increase pathway output? | PACAP overexpression cell line |
| Which genes regulate cAMP amplitude? | CRISPR library screening with cAMP reporters |
| How does endosomal signaling contribute to excitability? | Knock-in of trafficking-deficient receptor mutants |
How to Study the regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| cAMP accumulation assay | Intracellular cAMP levels | Quantifying pathway activation |
| FRET biosensor imaging | Real-time cAMP dynamics | Spatial and temporal regulation |
| RNA-seq | Transcriptome changes | Downstream gene expression programs |
| CRISPR knockout | Loss-of-function effects | Testing causal roles of receptors and G proteins |
| Knock-in reporter | Receptor localization and trafficking | Endosomal signaling studies |
| Phosphoproteomics | Kinase substrate changes | Mapping feedback regulation |
| Bioinformatic pathway enrichment | GO and pathway annotation | Linking genes to GO:0106070 |
cAMP and signaling assays
cAMP accumulation assays, FRET-based biosensors and luciferase reporter systems measure the output of adenylate cyclase-activating GPCR signaling. These methods are used to quantify how regulatory inputs change the frequency and extent of pathway activation.
Genetic and molecular perturbation
Knockout, knockdown and overexpression of ligands, receptors and G proteins are used to test causality in this pathway. Molecular and genetic studies of VIP and PACAP have established this approach as a standard way to dissect pathway regulation.
Imaging and trafficking analysis
Fluorescence imaging of tagged receptors and endosomal markers reveals where signaling occurs and how long it persists. Endosomal PAC1 signaling studies illustrate how imaging can uncover spatial regulation of the pathway.
Transcriptomic and bioinformatic analysis
RNA-seq and pathway enrichment can identify gene expression changes downstream of altered cAMP signaling. Such analyses help connect GO:0106070 to broader cellular programs in stress, metabolism and tissue-specific contexts.
How CRISPR Can Be Used to Study GO:0106070 regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
Knockout
CRISPR knockout of ADCYAP1R1, VIPR1, VIPR2 or GNAS can eliminate specific nodes of the pathway, allowing researchers to determine which components are required for adenylate cyclase activation and its regulation. Knockout models are also useful for testing whether a candidate regulator changes cAMP amplitude or duration.
Point Mutation
Point-mutation knock-in can model disease-associated variants in receptors or G proteins, revealing how single amino acid changes alter coupling, desensitization or endosomal signaling. This approach is valuable when a variant is suspected to affect pathway regulation without abolishing protein expression.
Knock-in
Tagged knock-in of PAC1 or VPAC receptors enables live-cell imaging of receptor trafficking and endosomal signaling, which are key regulatory mechanisms in GO:0106070. Knock-in of reporter cassettes can also provide readouts of pathway activity in specific cell types.
Overexpression
Overexpression of PACAP, VIP or their receptors can amplify pathway output and reveal rate-limiting steps in cAMP production. This is particularly useful for studying ligand-dependent regulation and for screening compounds that modulate the pathway.
How EDITGENE Supports regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Research
Researchers studying 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 shaping cAMP responses, receptor trafficking or downstream physiology. EDITGENE provides publication-ready CRISPR cell models and screening services designed to answer these questions with rigor and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway research.
Frequently Asked Questions About regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
What is GO:0106070?
GO:0106070 is the biological process term for regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, meaning any process that modulates the frequency, rate or extent of a GPCR pathway that activates adenylate cyclase.
What genes are involved in regulation of adenylate cyclase-activating GPCR signaling?
Key genes include ADCYAP1, VIP, ADCYAP1R1, VIPR1, VIPR2, GNAS and adenylate cyclase isoforms, as well as phosphodiesterases and arrestins that shape cAMP dynamics.
What does adenylate cyclase-activating GPCR signaling do?
It converts extracellular signals from ligands such as VIP and PACAP into intracellular cAMP, which then activates downstream kinases and transcription factors.
How is PACAP involved in this pathway?
PACAP is a ligand that binds PAC1, VPAC1 and VPAC2 receptors to stimulate adenylate cyclase and cAMP production, and its signaling is regulated at the receptor and endosomal levels.
Is GO:0106070 involved in disease?
Yes, dysregulation of this pathway has been linked to stress-related disorders, metabolic imbalance, reproductive dysfunction and cartilage pathology.
What research methods study this pathway?
Common methods include cAMP assays, FRET biosensors, RNA-seq, phosphoproteomics and CRISPR-based perturbation of receptors and G proteins.
Can CRISPR knockout help study this pathway?
Yes, CRISPR knockout of receptors, G proteins or adenylate cyclases can reveal which components are required for pathway regulation and downstream responses.
What is endosomal signaling in this pathway?
Endosomal signaling means the receptor continues to signal after internalization, which can prolong cAMP production and regulate neuronal excitability.
Which receptors activate adenylate cyclase?
Class B GPCRs such as PAC1, VPAC1 and VPAC2 couple to Gs and activate adenylate cyclase in response to VIP and PACAP.
Why is regulation of this pathway important for drug discovery?
Because cAMP signaling controls many physiological processes, modulating its regulators offers therapeutic opportunities in neurology, endocrinology and oncology.
Conclusion
GO:0106070 captures the regulatory control of one of the most important cAMP-generating pathways in cell biology. Its components, from VIP and PACAP ligands to PAC1, VPAC receptors, Gs and adenylate cyclases, are well defined, and its regulation occurs through ligand availability, receptor trafficking, endosomal signaling and feedback mechanisms. Studying this process with CRISPR models and functional assays can clarify disease mechanisms and support therapeutic development.
References
- 1. Moody TW et al.. 2011. VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies.. Curr Opin Endocrinol Diabetes Obes 18(1):61-7 PMID: 21157320
- 2. May V et al.. 2017. G Protein-Coupled Receptor Endosomal Signaling and Regulation of Neuronal Excitability and Stress Responses: Signaling Options and Lessons From the PAC1 Receptor.. J Cell Physiol 232(4):698-706 PMID: 27661062
- 3. Lauretta G et al.. 2020. Current knowledge of pituitary adenylate cyclase activating polypeptide (PACAP) in articular cartilage.. Histol Histopathol 35(11):1251-1262 PMID: 32542641
- 4. Maunze B et al.. 2022. Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis.. Am J Physiol Endocrinol Metab 322(3):E199-E210 PMID: 35001657
- 5. Winters SJ et al.. 2020. PACAP: A regulator of mammalian reproductive function.. Mol Cell Endocrinol 518:110912 PMID: 32561449
- 6. Kong L et al.. 2016. Pituitary Adenylate cyclase-activating polypeptide orchestrates neuronal regulation of the astrocytic glutamate-releasing mechanism system xc (.).. J Neurochem 137(3):384-93 PMID: 26851652
- 7. Langer I et al.. 2022. Signal Transduction by VIP and PACAP Receptors.. Biomedicines 10(2) PMID: 35203615
- 8. Rajbhandari AK et al.. 2023. The functional heterogeneity of PACAP: Stress, learning, and pathology.. Neurobiol Learn Mem 203:107792 PMID: 37369343
