GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway: cAMP Signaling, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0007189 describes a G protein-coupled receptor (GPCR) signaling pathway in which ligand binding leads to activation of adenylyl cyclase, raising intracellular cyclic AMP (cAMP).
• The pathway is negatively regulated by phosphodiesterases, which cleave cAMP and terminate the signal.
• Key receptors include PAC1 (ADCYAP1R1), VPAC1 (VIPR1), and VPAC2 (VIPR2), which are activated by PACAP and VIP neuropeptides.
• Downstream effectors include Gs alpha (GNAS), adenylyl cyclases (ADCY1-9), protein kinase A (PRKACA/B), and EPAC exchange factors.
• Dysregulation of this pathway is implicated in cancer, obesity, insulin resistance, addiction, migraine, and chemotherapy-induced neuropathic pain.
• CRISPR knockout, point-mutation, knock-in, and overexpression models enable causal dissection of GO:0007189 components in disease contexts.
Description
GO:0007189, adenylate cyclase-activating G protein-coupled receptor signaling pathway, is a biological process in which an extracellular ligand binds a G protein-coupled receptor (GPCR) that couples to the stimulatory G protein Gs, leading to activation of adenylyl cyclase and a rise in intracellular cyclic AMP (cAMP). This pathway is one of the most widely studied signal transduction cascades because cAMP serves as a universal second messenger controlling metabolism, gene expression, neuronal excitability, and cell proliferation. The QuickGO definition emphasizes that the signal is transmitted via activation of adenylyl cyclase activity and is negatively regulated by phosphodiesterases that cleave cAMP. Researchers study GO:0007189 to understand how hormones, neurotransmitters, and neuropeptides such as PACAP and VIP regulate physiology and to identify therapeutic targets in cancer, metabolic disease, and neurological disorders. The pathway is also a paradigm for GPCR pharmacology, including biased agonism, splice-variant signaling, and endosomal signaling.
adenylate cyclase-activating G protein-coupled receptor signaling pathway At A Glance
| GO ID | GO:0007189 |
|---|---|
| GO term | adenylate cyclase-activating G protein-coupled receptor signaling pathway |
| Ontology | biological_process |
| Synonym | activation of adenylate cyclase activity by G-protein signaling pathway; adenylate cyclase-activating GPCR signaling pathway; GPCR signaling pathway via activation of adenylate cyclase; G protein signaling, adenylate cyclase activating pathway |
| Major function | Transduces extracellular signals via Gs-coupled GPCRs to activate adenylyl cyclase, increasing intracellular cAMP and activating downstream effectors such as PKA and EPAC. |
| Negative regulation | Phosphodiesterases cleave cAMP and terminate the signal. |
| Key receptors | PAC1 (ADCYAP1R1), VPAC1 (VIPR1), VPAC2 (VIPR2). |
| Key effectors | GNAS, ADCY1-9, PRKACA, PRKACB, RAPGEF3 (EPAC1), RAPGEF4 (EPAC2). |
| Disease relevance | Cancer, obesity/insulin resistance, addiction, migraine, chemotherapy-induced cold allodynia. |
What Is GO:0007189?
In simple terms, GO:0007189 is the process where a signal outside the cell activates a GPCR that turns on adenylyl cyclase, making more cAMP inside the cell. According to QuickGO, it is a G protein-coupled receptor signaling pathway in which the signal is transmitted via the activation of adenylyl cyclase activity, resulting in an increase in the intracellular concentration of cyclic AMP (cAMP). The pathway is negatively regulated by phosphodiesterase, which cleaves cAMP and terminates the signaling.
Why Is adenylate cyclase-activating G protein-coupled receptor signaling pathway Important in Cell Biology?
GO:0007189 is important because it is a central mechanism by which hormones and neurotransmitters control cellular physiology, and its dysregulation contributes to major human diseases including cancer, metabolic disorders, and neurological conditions. Understanding this pathway enables rational design of drugs targeting GPCRs, adenylyl cyclases, and phosphodiesterases, and it provides a framework for studying biased agonism and signaling specificity.
• Controls cAMP-dependent processes such as metabolism, gene transcription, and neuronal excitability.
• Mediates the actions of neuropeptides PACAP and VIP, which regulate energy homeostasis and stress responses.
• Is implicated in cancer, where neuropeptide GPCRs can act as oncotargets.
• Plays a role in obesity-induced insulin resistance through PACAP signaling.
• Contributes to addiction-related behaviors via PACAP signaling.
• Is involved in migraine pathophysiology through PACAP and its receptor splice variants.
• Participates in chemotherapy-induced acute cold allodynia via spinal PACAP/PAC1 signaling.
• Provides targets for phosphodiesterase inhibitors and adenylyl cyclase modulators.
• Serves as a model for GPCR endosomal signaling and regulation of neuronal excitability.
• Enables CRISPR-based functional genomics of pathway components in disease models.
What Happens During adenylate cyclase-activating G protein-coupled receptor signaling pathway?
Ligand binding and receptor activation
In simple terms: A signaling molecule binds to a receptor on the cell surface, turning it on.
The pathway begins when an extracellular ligand such as PACAP or VIP binds to a Gs-coupled GPCR, including PAC1 (ADCYAP1R1), VPAC1 (VIPR1), or VPAC2 (VIPR2). This binding induces a conformational change in the receptor that enables it to act as a guanine nucleotide exchange factor for the Gs alpha subunit.
G protein activation and adenylyl cyclase stimulation
In simple terms: The activated receptor turns on a G protein, which then switches on an enzyme that makes cAMP.
Activated receptor promotes the exchange of GDP for GTP on GNAS (Gs alpha), causing dissociation of Gs alpha from G beta-gamma subunits. GTP-bound Gs alpha then binds and activates adenylyl cyclase (ADCY1-9), which catalyzes the conversion of ATP to cyclic AMP (cAMP).
cAMP effector activation
In simple terms: cAMP acts as a second messenger to activate downstream proteins.
Increased intracellular cAMP activates effectors including protein kinase A (PRKACA/PRKACB) and exchange proteins directly activated by cAMP (EPAC1/RAPGEF3 and EPAC2/RAPGEF4). These effectors propagate the signal by phosphorylating target proteins or activating small GTPases, influencing neuronal excitability, gene expression, and metabolism.
Termination by phosphodiesterases
In simple terms: Enzymes break down cAMP to stop the signal.
The pathway is negatively regulated by phosphodiesterases, which cleave cAMP to 5-AMP, thereby terminating the signaling. This termination step is essential for restoring basal cellular states and preventing sustained activation.
Endosomal signaling and splice variants
In simple terms: The signal can continue from inside the cell after the receptor is internalized, and different receptor forms can signal differently.
For the PAC1 receptor, endosomal signaling and distinct splice variants can recruit unique signaling pathways that contribute to neuronal excitability and stress responses. These mechanisms add complexity to GO:0007189 and are relevant to drug design targeting PACAP signaling.
Key Genes Involved in GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway
The following genes and proteins are core components or regulators of GO:0007189, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ADCYAP1R1 (PAC1) | Receptor for PACAP; activates Gs and adenylyl cyclase | Implicated in stress, pain, migraine, and energy homeostasis |
| VIPR1 (VPAC1) | Receptor for VIP and PACAP; Gs-coupled | Studied in cancer and neuropeptide signaling |
| VIPR2 (VPAC2) | Receptor for VIP and PACAP; Gs-coupled | Studied in cancer and neuropeptide signaling |
| ADCYAP1 (PACAP) | Ligand activating PAC1, VPAC1, VPAC2 | Involved in obesity, insulin resistance, addiction, and pain |
| VIP | Ligand activating VPAC1 and VPAC2 | Studied in physiology and disease |
| GNAS (Gs alpha) | G protein subunit that activates adenylyl cyclase | Central to cAMP signaling; mutated in various diseases |
| ADCY1-9 | Adenylyl cyclases that synthesize cAMP from ATP | Effector enzymes of the pathway |
| PRKACA | Catalytic subunit of protein kinase A; cAMP effector | Mediates phosphorylation downstream of cAMP |
| PRKACB | Catalytic subunit of protein kinase A; cAMP effector | Mediates phosphorylation downstream of cAMP |
| RAPGEF3 (EPAC1) | Exchange protein activated by cAMP | Regulates small GTPase signaling |
| RAPGEF4 (EPAC2) | Exchange protein activated by cAMP | Regulates small GTPase signaling |
| PDE4 | Phosphodiesterase that degrades cAMP | Terminates signaling; drug target |
| PDE3 | Phosphodiesterase that degrades cAMP | Terminates signaling; drug target |
| FAIM | Modulator in PACAP signaling pathway | Involved in insulin resistance via FAIM/Rictor/AKT axis |
| RICTOR | Component of mTORC2; interacts with FAIM | Mediates PACAP effects on insulin resistance |
| AKT | Kinase downstream of PACAP/FAIM/Rictor | Mediates metabolic effects |
| GNAI | Gi alpha; inhibits adenylyl cyclase | Provides negative regulation of cAMP |
| ARRB1/2 | Beta-arrestins; regulate GPCR desensitization and endosomal signaling | Modulate PAC1 signaling and trafficking |
How Is adenylate cyclase-activating G protein-coupled receptor signaling pathway Regulated?
GO:0007189 is regulated at multiple levels. Phosphodiesterases cleave cAMP and terminate the signal, providing negative regulation. G protein-coupled receptor kinases and beta-arrestins desensitize receptors and promote endosomal signaling, as shown for the PAC1 receptor. Splice variants of PAC1 can recruit unique signaling pathways, adding another layer of regulation. Additionally, PACAP signaling intersects with the FAIM/Rictor/AKT axis to modulate insulin resistance, linking the pathway to metabolic regulation.
adenylate cyclase-activating G protein-coupled receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ADCYAP1R1 | Pain, migraine, stress, energy homeostasis | Knockout mouse, point-mutation knock-in, conditional KO |
| ADCYAP1 | Obesity, insulin resistance, addiction | Overexpression, knockout, knock-in |
| VIPR1/VIPR2 | Cancer | Knockout, overexpression in cancer cell lines |
| GNAS | Metabolic and endocrine disorders | Point-mutation knock-in, knockout |
| PDE4 | Inflammatory and neurological disorders | Knockout, point-mutation, overexpression |
Cancer
Neuropeptide GPCRs that activate adenylyl cyclase, including PAC1, VPAC1, and VPAC2, are overexpressed in various cancers and have been proposed as oncotargets. Their signaling via cAMP can promote proliferation, survival, and migration, making GO:0007189 relevant to cancer biology and therapy.
Metabolic disease and obesity
PACAP ameliorates obesity-induced insulin resistance through the FAIM/Rictor/AKT axis, implicating GO:0007189 in metabolic regulation. PAC1 receptor activation in the hypothalamus recruits signaling pathways involved in energy homeostasis, suggesting a role in body weight control.
Addiction and stress
PACAP signaling has been described as the dark side of addiction, contributing to stress responses and addictive behaviors. The PAC1 receptor regulates neuronal excitability and stress responses via endosomal signaling, linking GO:0007189 to neuropsychiatric disorders.
Pain and migraine
Spinal PACAP and PAC1 receptor signaling are involved in oxaliplatin-induced acute cold allodynia in mice. PACAP signaling, including splice variants and designer drugs, is a key focus in migraine research.
From adenylate cyclase-activating G protein-coupled receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of ADCYAP1R1 affect pain sensitivity? | ADCYAP1R1 knockout mouse |
| Does a specific PAC1 splice variant mediate migraine-like behavior? | Knock-in of specific splice variant |
| Does PACAP overexpression improve insulin sensitivity? | Transgenic overexpression of ADCYAP1 |
| Does GNAS mutation alter cAMP signaling? | Point-mutation knock-in of GNAS |
| Does PDE4 inhibition enhance cAMP signaling? | PDE4 knockout or point-mutation |
| Does VPAC1/VPAC2 drive cancer cell proliferation? | Knockout and overexpression in cancer cell lines |
How to Study the adenylate cyclase-activating G protein-coupled receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| cAMP biosensor assay | Intracellular cAMP concentration | Measure pathway activation by ligands |
| Phosphoproteomics | Phosphorylation of downstream targets | Identify PKA substrates |
| Live-cell imaging | Receptor trafficking and cAMP dynamics | Study endosomal signaling |
| CRISPR knockout screen | Gene essentiality for pathway output | Discover regulators of cAMP |
| RNA-seq | Transcriptional changes | Assess downstream gene expression |
| Western blot | Protein expression and phosphorylation | Validate signaling changes |
| ELISA | Ligand or cAMP levels | Quantify pathway activity |
| Patch-clamp electrophysiology | Neuronal excitability | Study PAC1 effects on neurons |
cAMP measurement
Intracellular cAMP levels can be measured using luminescent or fluorescent biosensors, or ELISA-based assays, to directly assess activation of GO:0007189.
Phosphoproteomics
Phosphoproteomics can identify downstream targets of PKA and other cAMP effectors, revealing the signaling network activated by GO:0007189.
Live-cell imaging
Live-cell imaging of fluorescently tagged receptors and biosensors can track receptor trafficking, endosomal signaling, and cAMP dynamics in real time.
CRISPR screening
Genome-wide CRISPR knockout or activation screens can identify genes that regulate cAMP levels or downstream phenotypes, uncovering novel components of GO:0007189.
How CRISPR Can Be Used to Study GO:0007189 adenylate cyclase-activating G protein-coupled receptor signaling pathway
Knockout
CRISPR knockout of genes such as ADCYAP1R1, VIPR1, VIPR2, GNAS, or ADCY isoforms can abolish GO:0007189 signaling, enabling causal tests of their role in disease models.
Point Mutation
Point mutations can be introduced to mimic disease-associated variants or to dissect specific phosphorylation sites in pathway components, such as GNAS or PAC1.
Knock-in
Knock-in of tagged or reporter alleles allows tracking of receptor localization and signaling in vivo, as well as introduction of specific splice variants of PAC1.
Overexpression
Overexpression of ligands such as PACAP or VIP, or of receptors, can enhance GO:0007189 signaling and model gain-of-function states in cancer or metabolic disease.
How EDITGENE Supports adenylate cyclase-activating G protein-coupled receptor signaling pathway Research
Researchers studying adenylate cyclase-activating G protein-coupled receptor signaling pathway-related genes often need to determine whether a candidate gene is causally involved in pathway output, disease phenotypes, or drug responses. EDITGENE provides CRISPR-based cell models and screening services to enable such functional studies with high specificity and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for adenylate cyclase-activating G protein-coupled receptor signaling pathway research.
Frequently Asked Questions About adenylate cyclase-activating G protein-coupled receptor signaling pathway
What is GO:0007189?
GO:0007189 is the Gene Ontology term for adenylate cyclase-activating G protein-coupled receptor signaling pathway, a process where GPCRs activate adenylyl cyclase to increase cAMP.
What genes are involved in adenylate cyclase-activating GPCR signaling?
Key genes include ADCYAP1R1, VIPR1, VIPR2, GNAS, ADCY1-9, PRKACA, PRKACB, RAPGEF3, and RAPGEF4.
How is cAMP terminated in this pathway?
Phosphodiesterases cleave cAMP to 5-AMP, terminating the signal.
What diseases are linked to GO:0007189?
Cancer, obesity/insulin resistance, addiction, migraine, and chemotherapy-induced cold allodynia.
What is the role of PACAP in this pathway?
PACAP is a ligand that activates PAC1, VPAC1, and VPAC2 receptors, leading to adenylyl cyclase activation and cAMP increase.
How can I study GO:0007189 in the lab?
Use cAMP biosensors, phosphoproteomics, live-cell imaging, and CRISPR screens.
What CRISPR models are available for this pathway?
Knockout, point-mutation, knock-in, and overexpression models for receptors, G proteins, and effectors.
Is GO:0007189 involved in cancer?
Yes, neuropeptide GPCRs that activate adenylyl cyclase are overexpressed in cancers and are considered oncotargets.
What is the role of GNAS in this pathway?
GNAS encodes Gs alpha, which activates adenylyl cyclase upon GPCR stimulation.
How does PAC1 splice variation affect signaling?
Different PAC1 splice variants can recruit unique signaling pathways, influencing neuronal excitability and stress responses.
Conclusion
GO:0007189, adenylate cyclase-activating G protein-coupled receptor signaling pathway, is a fundamental biological process that converts extracellular signals into intracellular cAMP changes, controlling metabolism, neuronal function, and cell growth. Its dysregulation is implicated in cancer, metabolic disease, addiction, and pain, making it a rich area for therapeutic targeting. CRISPR-based models and functional genomics are powerful tools to dissect the causal roles of pathway components and to accelerate drug discovery.
References
- 1. Moody TW et al.. 2018. Neuropeptide G Protein-Coupled Receptors as Oncotargets.. Front Endocrinol (Lausanne) 9:345 PMID: 30008698
- 2. Feng J et al.. 2024. PACAP ameliorates obesity-induced insulin resistance through FAIM/Rictor/AKT axis.. FEBS J 291(18):4096-4110 PMID: 39041617
- 3. 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
- 4. Takasaki I et al.. 2025. Spinal pituitary adenylate cyclase-activating polypeptide and PAC1 receptor signaling system is involved in the oxaliplatin-induced acute cold allodynia in mice.. J Pain 27:104751 PMID: 39615811
- 5. 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
- 6. 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
- 7. Miles OW et al.. 2019. Pituitary Adenylate Cyclase-Activating Peptide (PACAP) Signaling and the Dark Side of Addiction.. J Mol Neurosci 68(3):453-464 PMID: 30074172
- 8. Tasma Z et al.. 2025. Decoding PACAP signaling: Splice variants, pathways and designer drugs.. Cephalalgia 45(8):3331024251363560 PMID: 40767099
