GO:0106071 positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0106071 describes any process that increases the frequency, rate, or extent of a G protein-coupled receptor signaling pathway that activates adenylate cyclase.
• The term is a biological process and is distinct from the upstream GPCR signaling pathway itself; it specifically covers positive regulatory inputs.
• Key molecular players include PACAP, VIP, their receptors (PAC1, VPAC1, VPAC2), dopamine D2 receptor, and the Gs alpha subunit [1,2,3,5,7,8].
• Dysregulation of this process is implicated in neurodevelopmental disorders, neurodegeneration, testicular degeneration, and cancer-related proliferation [2,4,5,7].
• CRISPR knockout, point mutation, knock-in, and overexpression models are essential to dissect causal roles of individual components in this pathway [1,2,3,5,7].
• EDITGENE provides end-to-end CRISPR cell model and library screening services to study positive regulation of adenylate cyclase-activating GPCR signaling [1,2,3,5,7].
Description
GO:0106071, positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, is a biological process ontology term that captures any event that enhances the activity of a GPCR pathway leading to increased adenylate cyclase activity and cyclic AMP production. This term is critical for understanding how extracellular signals are amplified or sustained in processes ranging from neurogenesis to hormone secretion [2,5,7]. Researchers studying this term aim to identify the specific ligands, receptors, and intracellular modifiers that positively regulate this signaling axis [1,3,6]. The pathway is highly relevant to human health because its dysregulation has been linked to developmental disorders, neurodegeneration, and cancer [2,4,5,7]. For example, PACAP and its receptor PAC1 are known to promote proliferation and astrogenesis in neural progenitor cells, a process that falls under positive regulation of adenylate cyclase-activating GPCR signaling. Similarly, VIP signaling has cardioprotective roles, and its positive regulation is essential for normal cardiac function. Understanding the molecular mechanisms and regulatory inputs of this process is therefore a major goal in cell biology and medicine [3,6,8].
positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway At A Glance
| GO ID | GO:0106071 |
|---|---|
| GO term | positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway |
| Ontology | biological_process |
| Synonym | positive regulation of adenylate cyclase-activating G-protein coupled receptor signaling pathway |
| Definition | Any process that activates or increases the frequency, rate or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway. |
| Major function | Enhances GPCR signaling that stimulates adenylate cyclase and cAMP production. |
| Related pathways | PACAP/PAC1, VIP/VPAC, dopamine D2 receptor signaling. |
| Key ligands | PACAP, VIP, dopamine. |
| Key receptors | PAC1, VPAC1, VPAC2, D2R. |
What Is GO:0106071?
According to the Gene Ontology, GO:0106071 is defined as any process that activates or increases the frequency, rate or extent of an adenylate cyclase-activating G protein-coupled receptor signaling pathway. In simpler terms, it covers all the positive regulatory events that boost a specific type of GPCR signaling, namely the one that turns on adenylate cyclase and raises cAMP levels. This term is a child of positive regulation of G protein-coupled receptor signaling pathway and is used to annotate gene products that enhance this signaling cascade.
Why Is positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Important in Cell Biology?
GO:0106071 is important because it defines the positive regulatory layer that controls the strength and duration of a major GPCR signaling pathway, which is essential for normal physiology and is frequently altered in disease [1,2,4,7]. By focusing on positive regulation, researchers can identify therapeutic targets that amplify beneficial signaling or dampen pathological overactivation [3,5,6].
• Regulates neurogenesis and neural progenitor proliferation through PACAP/PAC1 signaling [2,5,7].
• Controls hormone secretion in the pituitary, including PACAP expression in gonadotrophs.
• Modulates cardioprotective effects of VIP signaling.
• Is implicated in Alzheimer's disease-associated testis degeneration.
• Adapts to chronic hypoxia via upregulation of PACAP and its receptors in the carotid body.
• Influences cerebellar granule precursor cell proliferation in interaction with Sonic Hedgehog.
• Provides a mechanism for autocrine promotion of astrogenesis in neural progenitors.
• Serves as a target for understanding splice variant-specific signaling of PAC1 receptor.
• Offers opportunities for CRISPR-based functional genomics of GPCR signaling [1,2,3,5,7].
• Helps explain how extracellular signals are amplified in development and disease [2,4,5,7].
What Happens During positive regulation of 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.
Positive regulation begins with increased availability or binding of ligands such as PACAP or VIP to their cognate GPCRs, including PAC1, VPAC1, and VPAC2 [1,2,5,7]. This binding stabilizes the active receptor conformation and promotes G protein coupling. For example, PACAP/PAC1 autocrine signaling promotes proliferation and astrogenesis in neural progenitor cells. Dopamine D2 receptor activation can suppress PACAP expression, indicating that positive regulation is context-dependent and can be modulated by other GPCRs.
G protein activation and adenylate cyclase stimulation
In simple terms: The activated receptor turns on a G protein, which then switches on an enzyme that makes cAMP.
Activated receptors catalyze the exchange of GDP for GTP on the Gs alpha subunit, which then stimulates adenylate cyclase to produce cyclic AMP. Positive regulation of this step can occur through increased receptor density, enhanced G protein coupling efficiency, or reduced desensitization. Splice variants of the PACAP receptor differentially couple to G proteins, affecting the strength of adenylate cyclase activation.
Amplification of downstream signaling
In simple terms: The signal gets boosted inside the cell, leading to changes in gene expression and cell behavior.
Elevated cAMP activates protein kinase A and exchange proteins directly activated by cAMP, which propagate the signal to downstream targets that control proliferation, differentiation, and survival [2,5,7]. Positive regulation of this pathway can therefore amplify neurogenic and astrogenic responses in neural progenitors. In cerebellar granule precursors, PACAP and Sonic Hedgehog interact to control proliferation, illustrating cross-talk that enhances signaling output.
Physiological contexts of positive regulation
In simple terms: This process happens in many tissues, helping them respond to stress or developmental cues.
In the carotid body, chronic and intermittent hypoxia upregulate PACAP and its receptor expression, enhancing adenylate cyclase-activating signaling as an adaptive response. In the heart, VIP signaling exerts cardioprotective effects, and its positive regulation supports cardiac function under stress. In the testis, Alzheimer's disease-like pathology is associated with degeneration, suggesting that disrupted positive regulation may contribute to tissue damage.
Integration with other signaling pathways
In simple terms: This pathway does not work alone; it talks to other signals to fine-tune the response.
Positive regulation of adenylate cyclase-activating GPCR signaling intersects with Sonic Hedgehog signaling in cerebellar development and with dopamine D2 receptor signaling in the pituitary. These interactions can either synergize or antagonize the pathway, depending on cell type and developmental stage [3,5]. Such integration ensures that the positive regulation is appropriately timed and localized [5,7].
Key Genes Involved in GO:0106071 positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
The following genes and proteins are central to the positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ADCYAP1 | Encodes PACAP, a ligand that activates PAC1/VPAC receptors | Studied in neurogenesis, hypoxia adaptation, and pituitary function [2,5,6,7] |
| ADCYAP1R1 | Encodes PAC1 receptor, a GPCR that activates adenylate cyclase | Splice variants differentially regulate signaling |
| VIP | Encodes VIP, a ligand for VPAC receptors | Cardioprotective signaling |
| VIPR1 | Encodes VPAC1 receptor | Mediates VIP effects in various tissues |
| VIPR2 | Encodes VPAC2 receptor | Mediates VIP effects in various tissues |
| DRD2 | Encodes dopamine D2 receptor, which can modulate PACAP expression | Suppresses PACAP in gonadotrophs |
| GNAS | Encodes Gs alpha subunit, which stimulates adenylate cyclase | Central to signal transduction |
| ADCY1 | Encodes adenylate cyclase 1 | Produces cAMP downstream of Gs |
| ADCY2 | Encodes adenylate cyclase 2 | Produces cAMP downstream of Gs |
| ADCY3 | Encodes adenylate cyclase 3 | Produces cAMP downstream of Gs |
| ADCY4 | Encodes adenylate cyclase 4 | Produces cAMP downstream of Gs |
| ADCY5 | Encodes adenylate cyclase 5 | Produces cAMP downstream of Gs |
| ADCY6 | Encodes adenylate cyclase 6 | Produces cAMP downstream of Gs |
| ADCY7 | Encodes adenylate cyclase 7 | Produces cAMP downstream of Gs |
| ADCY8 | Encodes adenylate cyclase 8 | Produces cAMP downstream of Gs |
| ADCY9 | Encodes adenylate cyclase 9 | Produces cAMP downstream of Gs |
| PRKACA | Encodes protein kinase A catalytic subunit | Mediates downstream effects of cAMP [2,5,7] |
| SHH | Encodes Sonic Hedgehog, which interacts with PACAP signaling | Controls cerebellar granule precursor proliferation |
How Is positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Regulated?
The positive regulation of adenylate cyclase-activating GPCR signaling is itself regulated at multiple levels. Receptor expression levels can be upregulated, as seen for PACAP and its receptor in the carotid body during chronic hypoxia. Ligand availability is controlled by transcriptional and post-transcriptional mechanisms; for instance, dopamine D2 receptor activation suppresses PACAP expression in gonadotrophs. Splice variants of the PAC1 receptor provide differential signal transduction, allowing cells to fine-tune the positive regulation. Additionally, cross-talk with other pathways such as Sonic Hedgehog can modulate the strength of the signal. These regulatory layers ensure that the pathway is activated only when appropriate and for the correct duration [3,5,6,8].
positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ADCYAP1 | Neurodevelopmental disorders, hypoxia adaptation | Knockout mouse, overexpression cell lines [2,5,6,7] |
| ADCYAP1R1 | Neurological disorders, cancer | Point mutation knock-in, splice variant models |
| VIP | Cardiovascular disease | Knockout and overexpression models |
| DRD2 | Pituitary dysfunction | Knockout and point mutation models |
| SHH | Cerebellar developmental disorders | Knockout and conditional models |
Neurodevelopmental and neurodegenerative disorders
PACAP/PAC1 signaling positively regulates neurogenesis and astrogenesis, and its disruption has been linked to abnormal brain development [2,5,7]. In Alzheimer's disease mouse models, testis degeneration is observed, suggesting that neurodegenerative pathology can affect peripheral tissues where this pathway operates. The interaction between PACAP and Sonic Hedgehog in cerebellar development further highlights the importance of this pathway in neural disorders.
Cancer and proliferative disorders
Positive regulation of adenylate cyclase-activating GPCR signaling can promote cell proliferation in neural progenitors and other cell types [2,5,7]. Autocrine PACAP/PAC1 signaling drives proliferation and astrogenesis, which may contribute to tumorigenesis if deregulated. Therefore, components of this pathway are potential targets for cancer research [2,5,7].
Cardiovascular and metabolic diseases
VIP signaling, which activates adenylate cyclase via VPAC receptors, has cardioprotective roles. Positive regulation of this pathway may be beneficial in cardiovascular stress, but its overactivation could lead to metabolic imbalances. Understanding how this pathway is positively regulated could inform therapies for heart disease.
Hypoxia and tissue adaptation
Chronic and intermittent hypoxia upregulate PACAP and its receptor in the carotid body, enhancing adenylate cyclase-activating signaling as an adaptive response. Dysregulation of this process may contribute to hypoxia-related pathologies.
From positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of ADCYAP1 affect neurogenesis? | ADCYAP1 knockout mouse or CRISPR KO cell line [2,7] |
| How do PAC1 splice variants differentially signal? | Knock-in of specific splice variants in cell lines |
| Does dopamine D2 receptor regulate PACAP expression? | D2R knockout or knockdown in gonadotroph cells |
| What is the role of VIP in cardioprotection? | VIP overexpression or knockout in cardiac cells |
| How does hypoxia regulate PACAP receptor expression? | Carotid body cell models with hypoxia exposure |
| Does Sonic Hedgehog interact with PACAP signaling? | Double knockout or knockdown in cerebellar precursors |
How to Study the positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptome changes | Identify genes upregulated by pathway activation [2,3,6] |
| ChIP-seq | Protein-DNA interactions | Map transcription factor binding at target genes [2,3,6] |
| Phosphoproteomics | Phosphorylation events | Discover downstream kinase substrates [2,5,7] |
| Live-cell cAMP imaging | Intracellular cAMP dynamics | Measure real-time signaling kinetics |
| Proliferation assay | Cell growth | Assess effects on neural progenitors [2,5,7] |
| Differentiation assay | Cell fate changes | Evaluate astrogenesis or neurogenesis |
| Hypoxia exposure | Adaptive responses | Study carotid body signaling |
| CRISPR screening | Gene function at scale | Identify regulators of the pathway [1,2,3,5,7] |
Transcriptomic and epigenomic profiling
RNA-seq and ChIP-seq can identify genes and regulatory elements that are differentially expressed or bound when the pathway is positively regulated [2,3,6]. For example, hypoxia-induced upregulation of PACAP and its receptor can be detected by RNA-seq. These methods help map the transcriptional network downstream of positive regulation [2,3,6].
Proteomic and phosphoproteomic analysis
Mass spectrometry-based proteomics can quantify changes in protein abundance and phosphorylation status following pathway activation [2,5,7]. This is useful to identify downstream effectors of cAMP signaling, such as protein kinase A substrates [2,5,7].
Live-cell imaging of cAMP dynamics
Genetically encoded cAMP sensors can monitor real-time changes in intracellular cAMP levels upon positive regulation. This method allows researchers to assess the kinetics and amplitude of signaling in living cells.
Functional assays for proliferation and differentiation
Proliferation assays, differentiation markers, and cell fate analysis can determine the physiological outcomes of positive regulation [2,5,7]. For instance, neurosphere assays can measure neural progenitor proliferation in response to PACAP.
How CRISPR Can Be Used to Study GO:0106071 positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
Knockout
CRISPR knockout of genes such as ADCYAP1, ADCYAP1R1, or VIP can abolish positive regulation of adenylate cyclase-activating GPCR signaling, allowing researchers to test necessity [1,2,5,7]. For example, PACAP knockout reduces neural progenitor proliferation.
Point Mutation
Point mutations can be introduced to mimic disease-associated variants or to disrupt specific phosphorylation sites in receptors or G proteins. This helps dissect the precise molecular determinants of positive regulation.
Knock-in
Knock-in of tagged or reporter versions of key components, such as PAC1 receptor, enables visualization and quantification of receptor trafficking and signaling. Splice variant knock-ins can reveal differential signaling.
Overexpression
Overexpression of ligands like PACAP or VIP, or receptors like PAC1, can enhance positive regulation and amplify downstream responses [1,2,5,7]. This is useful to study gain-of-function effects in disease models [1,2,5,7].
How EDITGENE Supports positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway Research
Researchers studying positive 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 enhancing this signaling cascade. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models for such functional studies.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway research.
Frequently Asked Questions About positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway
What is GO:0106071?
GO:0106071 is the Gene Ontology term for positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, a biological process that enhances GPCR signaling leading to increased adenylate cyclase activity.
What genes are involved in positive regulation of adenylate cyclase-activating GPCR signaling?
Key genes include ADCYAP1, ADCYAP1R1, VIP, VIPR1, VIPR2, DRD2, GNAS, and various ADCY genes [1,2,3,5,7,8].
How does PACAP regulate this pathway?
PACAP binds to PAC1 receptor, activating Gs and adenylate cyclase, which increases cAMP and promotes neurogenesis and astrogenesis [2,5,7].
What is the role of dopamine D2 receptor in this pathway?
Dopamine D2 receptor activation can suppress PACAP expression in gonadotrophs, thereby modulating positive regulation.
Is this pathway involved in Alzheimer's disease?
Alzheimer's disease mouse models show testis degeneration, suggesting that neurodegenerative pathology may affect tissues where this pathway operates.
How is this pathway regulated by hypoxia?
Chronic and intermittent hypoxia upregulate PACAP and its receptor in the carotid body, enhancing adenylate cyclase-activating signaling.
What experimental models are used to study GO:0106071?
Knockout mice, CRISPR knockout cell lines, point mutation knock-ins, overexpression models, and live-cell imaging are commonly used [1,2,3,5,7,8].
What diseases are linked to dysregulation of this pathway?
Neurodevelopmental disorders, cancer, cardiovascular disease, and hypoxia-related pathologies have been linked [1,2,4,5,6,7].
How can CRISPR help study this pathway?
CRISPR knockout, point mutation, knock-in, and overexpression allow precise manipulation of genes to test their causal roles [1,2,3,5,7,8].
What services does EDITGENE offer for this pathway?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression cell models, library screening, and bioinformatics services [1,2,3,5,7,8].
Conclusion
GO:0106071, positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway, is a fundamental biological process that amplifies GPCR signaling through adenylate cyclase and cAMP. Its components, including PACAP, VIP, their receptors, and downstream effectors, are critical for neurogenesis, hormone secretion, cardioprotection, and adaptation to hypoxia [1,2,3,5,6,7,8]. Dysregulation of this pathway is associated with developmental, neurodegenerative, and cardiovascular diseases [1,2,4,5,6,7]. CRISPR-based models are indispensable for dissecting the causal roles of individual genes in this process. EDITGENE offers comprehensive services to accelerate such research.
References
- 1. Dvoráková MC. 2005. Cardioprotective role of the VIP signaling system.. Drug News Perspect 18(6):387-91 PMID: 16247516
- 2. 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
- 3. Winters SJ et al.. 2014. Dopamine-2 receptor activation suppresses PACAP expression in gonadotrophs.. Endocrinology 155(7):2647-57 PMID: 24823390
- 4. Szegeczki V et al.. 2020. Alzheimer's Disease Mouse as a Model of Testis Degeneration.. Int J Mol Sci 21(16) PMID: 32785075
- 5. 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
- 6. Lam SY et al.. 2012. Upregulation of pituitary adenylate cyclase activating polypeptide and its receptor expression in the rat carotid body in chronic and intermittent hypoxia.. Adv Exp Med Biol 758:301-6 PMID: 23080176
- 7. Nishimoto M et al.. 2007. PACAP/PAC1 autocrine system promotes proliferation and astrogenesis in neural progenitor cells.. Glia 55(3):317-27 PMID: 17115416
- 8. Spengler D et al.. 1993. Differential signal transduction by five splice variants of the PACAP receptor.. Nature 365(6442):170-5 PMID: 8396727
