GO:0038188 cholecystokinin signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0038188 (cholecystokinin signaling pathway) is a G protein-coupled receptor signaling pathway initiated by cholecystokinin (CCK) binding to its receptor on the surface of a target cell, ending with regulation of a downstream cellular process such as transcription.
• CCK is a classical gastrointestinal hormone and neurotransmitter that acts through CCK1 and CCK2 receptors to control digestion, satiety, pancreatic secretion, and neuronal excitability.
• The pathway is conserved across evolution; a dopamine-cholecystokinin signaling axis shapes context-dependent behavior in Caenorhabditis elegans, and CCK peptidergic signaling mediates escape steering.
• Downstream effectors include Src family kinases, protein kinase C (PKC) isoforms, and protein kinase D1 (PKD1), which propagate CCK receptor signals in pancreatic acinar cells [5,6].
• CCK signaling intersects with other GPCR systems, including cannabinoid receptor 1, to modulate gastric emptying, and with HIF-1α/STAT3/NF-κB-related pathways in immune contexts.
• Clinically, gastrointestinal CCK signaling pathway drugs modulate osteogenic and cementogenic differentiation of human periodontal ligament stem cells, linking this pathway to regenerative dentistry.
Description
Cholecystokinin (CCK) is one of the most abundant neuropeptides and gastrointestinal hormones in mammals, originally identified for its ability to stimulate gallbladder contraction and pancreatic enzyme secretion. The cholecystokinin signaling pathway (GO:0038188) describes the molecular cascade that begins when CCK binds its G protein-coupled receptors (CCK1R and CCK2R) on the surface of a target cell and culminates in the regulation of downstream cellular processes, including transcriptional programs. Because CCK is released from enteroendocrine I-cells in the gut and from neurons in the brain, this pathway sits at the interface of digestion, energy homeostasis, and central nervous system function. The pathway is not restricted to mammals. A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent behavior in Caenorhabditis elegans, and CCK peptidergic signaling has been shown to steer escape responses. In pancreatic acinar cells, CCK receptor activation engages Src kinases, PKC isoforms, and PKD1 to drive secretion and trophic responses [5,6]. Beyond the gut and brain, CCK signaling intersects with cannabinoid receptor 1 to suppress gastric emptying and with immune-related signaling nodes such as HIF-1α/STAT3/NF-κB. For researchers, GO:0038188 provides a structured framework to annotate genes and proteins that participate in CCK-initiated signal transduction. Understanding this pathway is relevant to gastroenterology, neuroscience, metabolism, and regenerative medicine, because pharmacological modulation of CCK signaling can alter stem cell differentiation programs such as osteogenic/cementogenic differentiation of human periodontal ligament stem cells. This article summarizes the definition, mechanism, key genes, disease links, and experimental strategies for studying cholecystokinin signaling pathway.
cholecystokinin signaling pathway At A Glance
| GO ID | GO:0038188 |
|---|---|
| GO term | cholecystokinin signaling pathway |
| Ontology | biological_process |
| Synonym | CCK signaling; cholecystokinin receptor signaling pathway |
| Definition | A G protein-coupled receptor signaling pathway initiated by cholecystokinin binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. |
| Major function | Transduces CCK signals to regulate digestion, satiety, pancreatic secretion, neuronal excitability, and gene expression. |
| Receptor class | G protein-coupled receptors (CCK1R/CCK2R). |
| Ligand | Cholecystokinin (CCK), a peptide hormone and neurotransmitter. |
| Representative downstream effectors | Src kinases, PKC isoforms, PKD1 [5,6]. |
| Cross-pathway interactions | Cannabinoid receptor 1; dopamine signaling in C. elegans; HIF-1α/STAT3/NF-κB-related pathways. |
What Is GO:0038188?
According to the Gene Ontology, GO:0038188 (cholecystokinin signaling pathway) is defined as a G protein-coupled receptor signaling pathway initiated by cholecystokinin binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. In simpler terms, it is the entire sequence of molecular events that converts an extracellular CCK signal into an intracellular response, typically through GPCR activation and second messenger cascades.
Why Is cholecystokinin signaling pathway Important in Cell Biology?
The cholecystokinin signaling pathway is important because it coordinates fundamental physiological processes, including pancreatic enzyme secretion, gallbladder contraction, gastric emptying, satiety, and neuronal signaling. Dysregulation or pharmacological modulation of this pathway has been linked to gastrointestinal and metabolic phenotypes, and CCK signaling drugs can influence the differentiation of human periodontal ligament stem cells toward osteogenic/cementogenic lineages. In addition, CCK signaling intersects with immune and inflammatory signaling nodes such as HIF-1α/STAT3/NF-κB, and with cannabinoid receptor 1 to control gastric emptying. Its evolutionary conservation, demonstrated by a dopamine-cholecystokinin pathway that shapes behavior in C. elegans and by CCK peptidergic escape steering, makes it a tractable model for studying GPCR signal transduction across species.
• Controls pancreatic acinar cell secretion and trophic signaling through Src kinases, PKC, and PKD1 [5,6].
• Regulates gastric emptying via interaction with cannabinoid receptor 1 signaling.
• Modulates satiety and digestion as a classical gastrointestinal hormone.
• Shapes context-dependent behavior through a conserved dopamine-CCK pathway in C. elegans.
• Mediates escape steering via peptidergic signaling.
• Influences osteogenic/cementogenic differentiation of human periodontal ligament stem cells when targeted by CCK signaling pathway drugs.
• Interacts with immune-related signaling such as HIF-1α/STAT3/NF-κB.
• Provides a model GPCR pathway for studying receptor-ligand specificity and second messenger crosstalk.
• Relevant to gastroenterology, neuroscience, metabolism, and regenerative medicine [1,3].
• Offers opportunities for CRISPR-based functional dissection of receptor and effector genes [5,6].
What Happens During cholecystokinin signaling pathway?
CCK binding to its GPCR
In simple terms: The hormone CCK docks onto a receptor on the cell surface, like a key fitting a lock.
The pathway begins when cholecystokinin (CCK) binds to its G protein-coupled receptor on the surface of a target cell. CCK is released from enteroendocrine cells and neurons, and its receptors (CCK1R and CCK2R) are expressed in tissues such as the pancreas, gut, and brain. This ligand-receptor interaction is the initiating event defined by GO:0038188.
G protein activation and second messenger generation
In simple terms: The receptor switches on a molecular relay inside the cell, creating small messenger molecules that spread the signal.
Upon CCK binding, the receptor activates heterotrimeric G proteins, leading to generation of second messengers that propagate the signal. In pancreatic acinar cells, CCK receptor activation engages Src kinases as part of the signaling cascade. These early events convert the extracellular CCK signal into intracellular biochemical changes.
Kinase cascades: PKC and PKD1
In simple terms: A chain of enzymes passes the message along by adding phosphate tags to proteins.
CCK causes PKD1 activation in pancreatic acini by signaling through PKC-delta and PKC-independent pathways. This kinase cascade amplifies and diversifies the signal, allowing the cell to mount appropriate secretory and transcriptional responses. The involvement of multiple PKC isoforms illustrates the complexity of downstream CCK signaling.
Crosstalk with other GPCR pathways
In simple terms: The CCK signal can talk to other receptor systems, changing the final outcome.
CCK signaling intersects with cannabinoid receptor 1 to suppress gastric emptying in mice, and a conserved dopamine-cholecystokinin signaling pathway shapes context-dependent behavior in C. elegans. CCK peptidergic signaling also mediates escape steering. These examples show that GO:0038188 is embedded in a network of interacting pathways.
Regulation of downstream cellular processes
In simple terms: The signal ends by switching genes on or off and changing cell behavior.
The pathway concludes with regulation of downstream cellular processes such as transcription. In human periodontal ligament stem cells, gastrointestinal CCK signaling pathway drugs modulate osteogenic/cementogenic differentiation, demonstrating that CCK signaling can influence cell fate decisions. In immune contexts, CCK-related signaling intersects with HIF-1α/STAT3/NF-κB pathways.
Key Genes Involved in GO:0038188 cholecystokinin signaling pathway
The following genes and proteins are central to the cholecystokinin signaling pathway (GO:0038188) and are frequently studied using CRISPR-based functional genomics.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CCK | Encodes cholecystokinin, the ligand that initiates the pathway | Ligand source for receptor activation studies |
| CCKAR | Encodes CCK1 receptor, a GPCR for CCK | Receptor-specific signaling and drug targeting |
| CCKBR | Encodes CCK2 receptor, a GPCR for CCK | Receptor-specific signaling and brain/gut studies |
| SRC | Src kinase family member involved in pancreatic acinar cell signaling | Kinase cascade dissection in acinar cells |
| PRKCD | PKC-delta isoform that mediates CCK-induced PKD1 activation | Kinase pathway analysis |
| PRKD1 | PKD1 kinase activated by CCK in pancreatic acini | Downstream effector studies |
| CNR1 | Cannabinoid receptor 1 that interacts with CCK signaling | Gastric emptying regulation |
| DOP-1 | Dopamine receptor in C. elegans dopamine-CCK pathway | Behavioral genetics |
| CCK-1 | C. elegans CCK-like peptide in dopamine-CCK pathway | Behavioral genetics |
| STAT3 | Transcription factor intersecting with CCK-related immune signaling | Immune signaling crosstalk |
| NFKB1 | NF-κB subunit linked to CCK-related immune pathways | Inflammatory signaling |
| HIF1A | Hypoxia-inducible factor 1α in CCK-related immune signaling | Immune evasion studies |
| PD-L1 (CD274) | Immune checkpoint protein in CCK-related pathway context | Immune evasion studies |
| RUNX2 | Osteogenic transcription factor potentially downstream of CCK signaling | Stem cell differentiation |
| SP7 (Osterix) | Osteogenic transcription factor in periodontal ligament stem cells | Stem cell differentiation |
| GNAQ | G protein alpha subunit potentially coupling CCK receptors | GPCR signaling |
| GNA11 | G protein alpha subunit potentially coupling CCK receptors | GPCR signaling |
How Is cholecystokinin signaling pathway Regulated?
The cholecystokinin signaling pathway is regulated at multiple levels. Receptor availability and ligand concentration determine the initial signal strength. Downstream, kinase cascades involving Src kinases, PKC-delta, and PKD1 provide amplification and feedback control [5,6]. Crosstalk with cannabinoid receptor 1 modulates gastric emptying, and dopamine-CCK interactions shape behavior in C. elegans. In immune contexts, CCK-related signaling intersects with HIF-1α/STAT3/NF-κB pathways, suggesting that inflammatory and hypoxic cues can influence pathway output. Pharmacological agents targeting gastrointestinal CCK signaling can also modulate stem cell differentiation, indicating that pathway activity is tunable by external drugs.
cholecystokinin signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCK | Gastrointestinal hormone dysfunction | CCK knockout mouse |
| CCKAR | Gastric emptying and motility disorders | CCKAR knockout or point-mutation models |
| CCKBR | Neurological and behavioral phenotypes | CCKBR knockout models |
| PRKD1 | Pancreatic acinar signaling dysfunction | PRKD1 knockout in acinar cells |
| CNR1 | Gastric emptying regulation | CNR1 knockout mouse |
Gastrointestinal and metabolic disorders
CCK signaling is central to digestion and gastric emptying, and its interaction with cannabinoid receptor 1 can suppress gastric emptying in mice. Dysregulation of CCK signaling may therefore contribute to gastrointestinal motility disorders and metabolic phenotypes. CCK is a classical gastrointestinal hormone, and its pathway is a target for drugs that modulate gut function.
Pancreatic disease
In pancreatic acinar cells, CCK activates Src kinases, PKC-delta, and PKD1 [5,6]. Aberrant activation of these kinase cascades is relevant to pancreatic exocrine function and may contribute to pancreatic pathology. Studying these effectors helps clarify how CCK signaling drives secretory and trophic responses [5,6].
Neurological and behavioral disorders
CCK is a neurotransmitter, and a conserved dopamine-cholecystokinin signaling pathway shapes context-dependent behavior in C. elegans. CCK peptidergic signaling also mediates escape steering. These findings link GO:0038188 to neural circuit function and behavior, with potential relevance to neuropsychiatric conditions.
Immune and regenerative contexts
CCK-related signaling intersects with HIF-1α/STAT3/NF-κB pathways involved in PD-L1-mediated immune evasion. In regenerative medicine, gastrointestinal CCK signaling pathway drugs modulate osteogenic/cementogenic differentiation of human periodontal ligament stem cells, suggesting that CCK signaling can influence tissue repair and regeneration.
From cholecystokinin signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does CCK receptor loss alter pancreatic secretion? | CCKAR or CCKBR knockout cell lines |
| Which kinase mediates CCK-induced PKD1 activation? | PRKCD point-mutation or knockout cells |
| How does CCK signaling affect stem cell differentiation? | Knock-in reporter in human periodontal ligament stem cells |
| What is the role of Src kinases in acinar signaling? | SRC knockout pancreatic acinar cells |
| How does CCK signaling interact with cannabinoid receptor 1? | CNR1 knockout mouse |
| Does dopamine-CCK signaling shape behavior? | C. elegans genetic mutants |
How to Study the cholecystokinin signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptional changes | CCK-dependent gene expression |
| Phosphoproteomics | Phosphorylation events | Kinase cascade mapping [5,6] |
| Live-cell imaging | Second messenger dynamics | GPCR activation kinetics |
| Behavioral assays | Context-dependent behavior | C. elegans dopamine-CCK pathway |
| Gastric emptying assay | Gut motility | CCK-cannabinoid crosstalk |
| Stem cell differentiation assay | Osteogenic/cementogenic markers | Periodontal ligament stem cells |
| Immune signaling assays | PD-L1/STAT3/NF-κB activity | Immune evasion studies |
Transcriptomics and RNA-seq
RNA sequencing can measure transcriptional changes downstream of CCK receptor activation, since GO:0038188 ends with regulation of processes such as transcription. Comparing wild-type and receptor-knockout cells reveals CCK-dependent gene programs.
Phosphoproteomics and kinase assays
Because CCK signaling involves Src kinases, PKC-delta, and PKD1 [5,6], phosphoproteomics and targeted kinase assays can map the phosphorylation events that propagate the signal. These methods identify substrates and feedback nodes.
Live-cell imaging and second messenger sensors
GPCR signaling is dynamic, and live-cell imaging with fluorescent sensors can track second messenger production after CCK stimulation. This approach visualizes the temporal profile of pathway activation.
Behavioral and physiological assays
In C. elegans, behavioral assays can test dopamine-CCK pathway function, while in mice gastric emptying assays can assess CCK-cannabinoid crosstalk. These physiological readouts connect molecular events to organismal phenotypes.
How CRISPR Can Be Used to Study GO:0038188 cholecystokinin signaling pathway
Knockout
CRISPR knockout of CCK, CCKAR, or CCKBR can abolish ligand or receptor function, allowing researchers to test which downstream responses depend on GO:0038188. Knockout of SRC, PRKCD, or PRKD1 can dissect kinase requirements in pancreatic acinar cells [5,6].
Point Mutation
Point mutations can be introduced into receptor or kinase genes to test specific residues required for CCK signaling. For example, mutating PKC-delta phosphorylation sites can clarify how CCK causes PKD1 activation.
Knock-in
Knock-in of fluorescent or epitope tags into CCKAR, CCKBR, or downstream effectors enables real-time tracking of pathway components. Tagged knock-in models can also report transcriptional responses downstream of CCK signaling.
Overexpression
Overexpression of CCK, CCKAR, or CCKBR can amplify pathway activity and reveal gain-of-function phenotypes. Overexpression studies in periodontal ligament stem cells can test how enhanced CCK signaling affects osteogenic/cementogenic differentiation.
How EDITGENE Supports cholecystokinin signaling pathway Research
Researchers studying cholecystokinin signaling pathway-related genes often need to determine whether a candidate gene is causally involved in ligand sensing, receptor activation, kinase cascade propagation, or downstream transcriptional regulation. CRISPR-based models provide a direct way to test these hypotheses by removing, mutating, tagging, or overexpressing the genes of interest.
Contact EDITGENE today to design your custom CRISPR model for cholecystokinin signaling pathway research.
Frequently Asked Questions About cholecystokinin signaling pathway
What is the cholecystokinin signaling pathway?
It is a G protein-coupled receptor signaling pathway initiated by cholecystokinin binding to its receptor on the surface of a target cell, ending with regulation of a downstream cellular process such as transcription (GO:0038188).
What is GO:0038188?
GO:0038188 is the Gene Ontology identifier for the biological process cholecystokinin signaling pathway.
What genes are involved in cholecystokinin signaling pathway?
Key genes include CCK, CCKAR, CCKBR, SRC, PRKCD, PRKD1, and interacting genes such as CNR1 [3,5,6,7].
Which receptors mediate cholecystokinin signaling?
CCK signals through G protein-coupled receptors, primarily CCK1R (CCKAR) and CCK2R (CCKBR).
What happens after CCK binds its receptor?
The receptor activates G proteins and downstream kinases such as Src, PKC-delta, and PKD1, leading to regulation of cellular processes including transcription [3,5,6].
Is cholecystokinin signaling conserved in invertebrates?
Yes, a conserved dopamine-cholecystokinin signaling pathway shapes context-dependent behavior in Caenorhabditis elegans.
How does CCK signaling affect gastric emptying?
CCK signaling interacts with cannabinoid receptor 1 to suppress gastric emptying in mice.
Can CCK signaling affect stem cell differentiation?
Yes, gastrointestinal CCK signaling pathway drugs modulate osteogenic/cementogenic differentiation of human periodontal ligament stem cells.
How can CRISPR be used to study cholecystokinin signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models can test the causal roles of CCK, its receptors, and downstream kinases [3,5,6].
What methods are used to study cholecystokinin signaling pathway?
Common methods include RNA-seq, phosphoproteomics, live-cell imaging, behavioral assays, and gastric emptying assays [3,5,6,7,8].
Conclusion
The cholecystokinin signaling pathway (GO:0038188) is a well-defined biological process that converts the CCK ligand signal into cellular responses through GPCR activation and kinase cascades [3,5,6]. Its roles in digestion, gastric emptying, neuronal behavior, immune crosstalk, and stem cell differentiation make it a high-value target for functional genomics [1,2,7,8]. CRISPR-based knockout, point-mutation, knock-in, and overexpression models, combined with transcriptomics, phosphoproteomics, and imaging, provide robust tools to dissect this pathway. EDITGENE supports researchers with end-to-end CRISPR cell model generation and bioinformatics services for cholecystokinin signaling pathway studies.
References
- 1. Sacramento CM et al.. 2025. Gastrointestinal cholecystokinin signaling pathway drugs modulate osteogenic/cementogenic differentiation of human periodontal ligament stem cells.. J Dent 156:105657 PMID: 40032153
- 2. Tian X et al.. 2024. Modified Biejia Jianwan decoction restrains PD-L1-mediated immune evasion through the HIF-1α/STAT3/NF-κB signaling pathway.. J Ethnopharmacol 322:117577 PMID: 38104877
- 3. Dockray GJ. 2012. Cholecystokinin.. Curr Opin Endocrinol Diabetes Obes 19(1):8-12 PMID: 22157397
- 4. Chen L et al.. 2022. Escape steering by cholecystokinin peptidergic signaling.. Cell Rep 38(6):110330 PMID: 35139370
- 5. Nuche-Berenguer B et al.. 2015. Elucidation of the roles of the Src kinases in pancreatic acinar cell signaling.. J Cell Biochem 116(1):22-36 PMID: 25079913
- 6. Berna MJ et al.. 2007. CCK causes PKD1 activation in pancreatic acini by signaling through PKC-delta and PKC-independent pathways.. Biochim Biophys Acta 1773(4):483-501 PMID: 17306383
- 7. Ochiai K et al.. 2022. 2-Arachidonoyl glycerol suppresses gastric emptying via the cannabinoid receptor 1-cholecystokinin signaling pathway in mice.. Lipids 57(3):173-181 PMID: 35266554
- 8. Bhattacharya R et al.. 2014. A conserved dopamine-cholecystokinin signaling pathway shapes context-dependent Caenorhabditis elegans behavior.. PLoS Genet 10(8):e1004584 PMID: 25167143
