GO:0106128 negative regulation of store-operated calcium entry: Calcium Signaling Brake, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0106128 describes any process that stops, prevents or reduces the frequency, rate or extent of store-operated calcium entry (SOCE), the calcium influx triggered when endoplasmic reticulum (ER) calcium stores are depleted.
• The core molecular players are the ER calcium sensor STIM1, the plasma membrane channel ORAI1, and the SOCE inhibitor SARAF, which promotes slow calcium-dependent inactivation of the STIM1-ORAI1 complex.
• Negative regulation of SOCE is essential to prevent calcium overload, shape oscillatory calcium signals, and control downstream effectors such as calcineurin-NFAT and Aurora A.
• Dysregulated SOCE and its negative control are implicated in triple-negative breast cancer (TNBC) metastasis, apoptosis resistance, and primary ciliogenesis defects.
• Pharmacological and optogenetic tools that modulate SOCE, including CRAC channel-based optogenetics, allow precise dissection of negative regulatory mechanisms.
• CRISPR knockout, point-mutation, knock-in, and overexpression cell models are key to causally testing genes that negatively regulate SOCE.
Description
Store-operated calcium entry (SOCE) is a ubiquitous calcium influx pathway activated when calcium is depleted from the endoplasmic reticulum (ER). It is mediated by the ER calcium sensor STIM1 and the plasma membrane calcium channel ORAI1. Because unrestrained SOCE can lead to cytotoxic calcium overload and inappropriate activation of calcium-dependent signaling, cells have evolved multiple mechanisms to negatively regulate this process. GO:0106128, negative regulation of store-operated calcium entry, captures any process that stops, prevents or reduces the frequency, rate or extent of SOCE.
negative regulation of store-operated calcium entry At A Glance
| GO ID | GO:0106128 |
|---|---|
| GO term | negative regulation of store-operated calcium entry |
| Ontology | biological_process |
| Synonym | none |
| Major function | Dampening or terminating calcium influx through STIM1-ORAI1 after ER calcium store depletion |
| Key regulators | SARAF, STIM1, ORAI1, TRPC6, AMPK |
| Associated diseases | Triple-negative breast cancer, metastasis, apoptosis resistance |
| Research methods | CRISPR KO, knock-in, overexpression, calcium imaging, optogenetics |
What Is GO:0106128?
GO:0106128 (negative regulation of store-operated calcium entry) is a biological process term defined as any process that stops, prevents or reduces the frequency, rate or extent of store-operated calcium entry. In practice, this includes protein-protein interactions, post-translational modifications, and signaling events that dampen the activation of STIM1-ORAI1-dependent calcium influx after ER calcium store depletion.
Why Is negative regulation of store-operated calcium entry Important in Cell Biology?
Negative regulation of SOCE is critical because excessive or prolonged calcium influx can trigger cell death, while insufficient negative regulation can sustain pathological calcium signaling that drives cancer progression, immune dysfunction, and other diseases. Understanding how SOCE is turned off or dampened provides therapeutic opportunities, particularly in cancers where SOCE components are dysregulated.
• Prevents calcium overload and excitotoxicity in cells with high SOCE activity.
• Shapes the amplitude and duration of calcium oscillations that control gene expression.
• Regulates calcineurin-NFAT signaling and other calcium-dependent transcription programs.
• Modulates primary ciliogenesis through Aurora A activation.
• Influences triple-negative breast cancer metastasis and apoptosis sensitivity.
• Is a target for pharmacological intervention in cancer and other SOCE-related diseases.
• Provides a mechanism for exercise-induced metabolic regulation via AMPK.
• Can be studied with optogenetic control of CRAC channels.
• Involves SARAF as a key negative regulator of STIM1-ORAI1.
• Melatonin can downregulate TRPC6 and impair SOCE in cancer cells.
What Happens During negative regulation of store-operated calcium entry?
Initiation of SOCE and the need for negative regulation
In simple terms: When calcium stores in the ER run low, STIM1 activates ORAI1 channels to let calcium in, but this must be controlled.
Upon ER calcium depletion, STIM1 oligomerizes and translocates to ER-plasma membrane junctions, where it activates ORAI1 channels to mediate SOCE. Without negative regulation, this influx would be sustained and potentially toxic, so cells engage inhibitory mechanisms.
SARAF-mediated slow calcium-dependent inactivation
In simple terms: SARAF is a protein that binds STIM1 and gradually shuts down calcium entry.
SARAF (SOCE-associated regulatory factor) interacts with STIM1 and promotes slow calcium-dependent inactivation of SOCE, thereby reducing the frequency and extent of calcium influx. The cytoplasmic region of SARAF is sufficient to reduce triple-negative breast cancer metastasis through regulation of SOCE.
Phosphorylation and AMPK-dependent modulation
In simple terms: Chemical tags like phosphate groups can change how SOCE is regulated.
Phosphoproteomics has revealed conserved exercise-stimulated signaling and AMPK regulation of SOCE, indicating that metabolic kinases can negatively regulate this pathway. This provides a link between cellular energy status and calcium entry control.
TRPC6 downregulation and melatonin effects
In simple terms: Melatonin can reduce the levels of TRPC6, a channel that contributes to calcium entry.
Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells, demonstrating hormonal negative regulation of SOCE.
Optogenetic control of CRAC channels
In simple terms: Light can be used to switch calcium channels on or off.
CRAC channel-based optogenetics enables precise temporal control of SOCE, allowing researchers to study negative regulation by turning the pathway on and off with light.
Key Genes Involved in GO:0106128 negative regulation of store-operated calcium entry
The following genes and proteins are central to the negative regulation of store-operated calcium entry.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SARAF | Binds STIM1 and promotes slow calcium-dependent inactivation of SOCE | Key negative regulator; target for cancer metastasis studies |
| STIM1 | ER calcium sensor that activates ORAI1 | Core SOCE activator; regulated by SARAF |
| ORAI1 | Plasma membrane calcium channel mediating SOCE | Effector of SOCE; target of negative regulation |
| TRPC6 | Non-selective cation channel contributing to SOCE | Downregulated by melatonin, impairing SOCE |
| AMPK | Metabolic kinase that regulates SOCE | Links energy status to SOCE negative regulation |
| Aurora A | Mitotic kinase activated by SOCE | Mediates SOCE inhibition of primary ciliogenesis |
| TP53 | Tumor suppressor; mutation affects SOCE | TP53 mutation-specific dysregulation of SOCE in TNBC |
| NFAT | Calcium-dependent transcription factor | Downstream effector of SOCE |
| Calcineurin | Calcium-dependent phosphatase | Activates NFAT downstream of SOCE |
| STIM2 | ER calcium sensor related to STIM1 | May modulate SOCE and its negative regulation |
| CRAC channel | Calcium release-activated calcium channel | Target of optogenetic control |
| SOCE-associated proteins | Various modulators of SOCE | Potential therapeutic targets |
| Melatonin receptor | Mediates melatonin effects on TRPC6 | Hormonal regulation of SOCE |
| Exercise-induced signaling factors | Mediate AMPK regulation of SOCE | Physiological negative regulation |
| Triple-negative breast cancer markers | Context for SOCE dysregulation | Disease relevance |
| Primary cilia components | Affected by SOCE via Aurora A | Ciliogenesis regulation |
How Is negative regulation of store-operated calcium entry Regulated?
Negative regulation of SOCE is itself regulated by calcium-dependent inactivation, phosphorylation events, and metabolic signals. SARAF promotes slow calcium-dependent inactivation of STIM1-ORAI1. AMPK, activated by exercise or energy stress, can negatively regulate SOCE. Melatonin downregulates TRPC6, impairing SOCE in cancer cells. These layers of regulation ensure that SOCE is tightly controlled in time and space.
negative regulation of store-operated calcium entry and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SARAF | TNBC metastasis | SARAF knockout and overexpression in TNBC cell lines |
| TP53 | TNBC apoptosis resistance | TP53 mutant knock-in TNBC cells |
| TRPC6 | TNBC SOCE impairment | TRPC6 knockdown or overexpression with melatonin treatment |
| ORAI1 | Cancer calcium signaling | ORAI1 point mutations and knock-in |
| STIM1 | SOCE-related diseases | STIM1 knockout and rescue |
Triple-negative breast cancer (TNBC)
TNBC cells often exhibit dysregulated SOCE. SARAF reduces TNBC metastasis through regulation of SOCE. TP53 mutation-specific dysregulation of SOCE and apoptotic sensitivity has been observed in TNBC. Melatonin impairs SOCE in TNBC cells by downregulating TRPC6.
Cancer therapeutic targeting
SOCE-based targets are being explored for novel cancer therapeutic development, highlighting the importance of negative regulation in preventing pathological calcium signaling.
Primary ciliogenesis defects
SOCE inhibits primary ciliogenesis via activation of Aurora A, linking negative regulation of SOCE to ciliary biology.
From negative regulation of store-operated calcium entry-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does SARAF negatively regulate SOCE? | SARAF knockout and overexpression cell lines |
| How does TP53 mutation affect SOCE? | TP53 mutant knock-in TNBC cells |
| Can optogenetics control SOCE? | CRAC channel-based optogenetic models |
| Does AMPK regulate SOCE? | AMPK knockout or knock-in cells |
| Does melatonin affect TRPC6 and SOCE? | TRPC6 knockdown/overexpression with melatonin |
| Does SOCE inhibit ciliogenesis? | Aurora A knockout or knock-in cells |
How to Study the negative regulation of store-operated calcium entry Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Calcium imaging | Intracellular calcium concentration | SOCE amplitude and kinetics |
| Optogenetics | Light-controlled SOCE | Temporal control of SOCE |
| Phosphoproteomics | Phosphorylation changes | Identify regulatory phosphorylation |
| CRISPR knockout | Gene function loss | Test negative regulators |
| Overexpression | Gain of function | Test SARAF, TRPC6 |
| RNA-seq | Transcriptional changes | Downstream effects of SOCE |
| Proteomics | Protein interactions | Identify STIM1-ORAI1 complexes |
Calcium imaging
Calcium imaging with fluorescent dyes or genetically encoded indicators measures SOCE dynamics and the effect of negative regulators.
Optogenetics
CRAC channel-based optogenetics allows light-controlled activation of SOCE, enabling precise study of negative regulation.
Phosphoproteomics
Phosphoproteomics identifies phosphorylation events that regulate SOCE, such as AMPK-dependent signaling.
CRISPR screening
CRISPR library screening can identify novel negative regulators of SOCE.
How CRISPR Can Be Used to Study GO:0106128 negative regulation of store-operated calcium entry
Knockout
CRISPR knockout of SARAF, STIM1, ORAI1, or TRPC6 can reveal their roles in negative regulation of SOCE.
Point Mutation
Point mutations in STIM1 or ORAI1 can dissect domains required for negative regulation.
Knock-in
Knock-in of tagged SARAF or STIM1 allows live-cell imaging of SOCE regulation.
Overexpression
Overexpression of SARAF or TRPC6 can enhance or impair SOCE, respectively.
How EDITGENE Supports negative regulation of store-operated calcium entry Research
Researchers studying negative regulation of store-operated calcium entry-related genes often need to determine whether a candidate gene is causally involved in SOCE control. EDITGENE provides CRISPR-based cell model services to enable such causal studies.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of store-operated calcium entry research.
Frequently Asked Questions About negative regulation of store-operated calcium entry
What is negative regulation of store-operated calcium entry?
It is any process that stops, prevents or reduces the frequency, rate or extent of store-operated calcium entry, often mediated by proteins like SARAF.
What genes are involved in negative regulation of store-operated calcium entry?
Key genes include SARAF, STIM1, ORAI1, TRPC6, and AMPK.
How does SARAF regulate SOCE?
SARAF binds STIM1 and promotes slow calcium-dependent inactivation of SOCE.
What diseases are linked to SOCE dysregulation?
Triple-negative breast cancer, metastasis, and ciliogenesis defects are linked to SOCE dysregulation.
Can CRISPR be used to study negative regulation of SOCE?
Yes, CRISPR knockout, knock-in, and overexpression models are widely used.
What is the role of AMPK in SOCE?
AMPK negatively regulates SOCE, linking energy status to calcium entry.
How does melatonin affect SOCE?
Melatonin downregulates TRPC6, impairing SOCE in triple-negative breast cancer cells.
What is optogenetic control of SOCE?
It uses light to control CRAC channels, enabling precise study of SOCE regulation.
What are the research methods for studying negative regulation of SOCE?
Calcium imaging, optogenetics, phosphoproteomics, and CRISPR screening are common.
Why is negative regulation of SOCE important?
It prevents calcium overload and shapes calcium-dependent signaling, with implications for cancer and other diseases.
Conclusion
Negative regulation of store-operated calcium entry (GO:0106128) is a critical biological process that prevents calcium overload and fine-tunes calcium signaling. Key regulators such as SARAF, STIM1, ORAI1, TRPC6, and AMPK are implicated in cancer and other diseases. CRISPR-based cell models from EDITGENE enable causal studies of these regulators.
References
- 1. Dagan I et al.. 2021. Regulation of Store-Operated Ca(2+) Entry by SARAF.. Cells 10(8) PMID: 34440656
- 2. Lai YS et al.. 2024. Store-operated calcium entry inhibits primary ciliogenesis via the activation of Aurora A.. FEBS J 291(5):1027-1042 PMID: 38050648
- 3. Nguyen NT et al.. 2018. CRAC channel-based optogenetics.. Cell Calcium 75:79-88 PMID: 30199756
- 4. Rabab KE et al.. 2025. TP53 Mutation-Specific Dysregulation of Store-Operated Calcium Entry and Apoptotic Sensitivity in Triple-Negative Breast Cancer.. Cancers (Basel) 17(10) PMID: 40427112
- 5. Hala'ufia ME et al.. 2025. Store-operated calcium entry-based targets for novel cancer therapeutic development.. J Pharmacol Exp Ther 392(10):103682 PMID: 41033085
- 6. Saldías MP et al.. 2023. The Cytoplasmic Region of SARAF Reduces Triple-Negative Breast Cancer Metastasis through the Regulation of Store-Operated Calcium Entry.. Int J Mol Sci 24(6) PMID: 36982380
- 7. Jardin I et al.. 2021. Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells.. J Biol Chem 296:100254 PMID: 33380424
- 8. Nelson ME et al.. 2019. Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry.. EMBO J 38(24):e102578 PMID: 31381180
