GO:1901341 positive regulation of store-operated calcium channel activity: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1901341 describes any process that activates or increases the frequency, rate or extent of store-operated calcium channel activity [1,2].
• Store-operated calcium entry (SOCE) is primarily mediated by STIM1 and ORAI1, and positive regulators such as TSPAN18 and CLCA2 enhance this pathway [1,2].
• Dysregulated SOCE positive regulation contributes to diseases including prostate cancer bone metastasis, rheumatoid arthritis, Alzheimer's disease, and diabetic osteoporosis [1,4,6,7].
• Key positive regulators include TSPAN18, CLCA2, and p21-activated kinase 1 (PAK1), which modulate STIM1 stability, TMEM16A activity, and nascent adhesion dynamics [1,2,3].
• Experimental models for studying GO:1901341 include knockout, point-mutation, knock-in, and overexpression cell lines, as well as CRISPR library screening [1,2,3,4,5,6,7,8].
• Understanding positive regulation of SOCE offers therapeutic targets for cancer, neurodegenerative, and metabolic disorders [1,4,6,8].
Description
Store-operated calcium channel activity is a fundamental cellular process that replenishes intracellular calcium stores following endoplasmic reticulum (ER) depletion [1,2]. The Gene Ontology term GO:1901341, positive regulation of store-operated calcium channel activity, encompasses any process that activates or increases the frequency, rate or extent of this channel activity [1,2]. This regulation is critical for diverse physiological functions, including immune cell activation, neuronal signaling, and bone remodeling [4,5,7]. Researchers study this term to understand how cells fine-tune calcium entry in health and disease, as its dysregulation is implicated in cancer progression, autoimmune disorders, and neurodegeneration [1,6,7]. The positive regulation of SOCE involves a complex interplay of proteins such as STIM1, ORAI1, and modulators like TSPAN18 and CLCA2 [1,2]. Investigating these mechanisms provides insights into cellular signaling and identifies potential therapeutic targets [3,8].
positive regulation of store-operated calcium channel activity At A Glance
| GO ID | GO:1901341 |
|---|---|
| GO term | positive regulation of store-operated calcium channel activity |
| Ontology | biological_process |
| Synonym | activation of store-operated calcium channel activity, up regulation of store-operated calcium channel activity, up-regulation of store-operated calcium channel activity, upregulation of store-operated calcium channel activity |
| Major function | Enhances store-operated calcium entry (SOCE) by modulating STIM1-ORAI1 interactions and channel gating [1,2]. |
| Key regulators | TSPAN18, CLCA2, PAK1, and other proteins that stabilize or activate SOCE components [1,2,3]. |
| Associated diseases | Prostate cancer bone metastasis, rheumatoid arthritis, Alzheimer's disease, diabetic osteoporosis, and remifentanil-induced hyperalgesia [1,4,6,7,8]. |
| Research methods | CRISPR knockout, point mutation, knock-in, overexpression, calcium imaging, and electrophysiology [1,2,3,4,5,6,7,8]. |
What Is GO:1901341?
GO:1901341 is a biological process term defined as any process that activates or increases the frequency, rate or extent of store-operated calcium channel activity [1,2]. In other words, it covers the molecular events that enhance the opening of calcium channels in response to depletion of intracellular calcium stores, primarily in the ER [1,2].
Why Is positive regulation of store-operated calcium channel activity Important in Cell Biology?
Positive regulation of store-operated calcium channel activity is essential for maintaining calcium homeostasis and signaling fidelity in numerous cell types [1,2]. It controls processes such as T cell activation, synaptic plasticity, and bone metabolism, and its dysregulation is linked to cancer, autoimmune diseases, and neurological disorders [1,4,6,7]. Understanding this term helps researchers identify therapeutic targets and develop interventions for these conditions [3,8].
• Enables sustained calcium signaling required for immune responses and inflammation [4,7].
• Promotes cancer cell survival and metastasis, as seen in prostate cancer bone metastasis.
• Contributes to neuronal function and is implicated in Alzheimer's disease pathology [5,6].
• Regulates bone remodeling and is involved in diabetic osteoporosis.
• Modulates pain sensitivity and hyperalgesia.
• Provides targets for drug development in autoimmune and metabolic diseases [4,7].
• Essential for T cell differentiation and function [4,7].
• Influences gene expression through calcium-dependent pathways.
• Plays a role in cell adhesion dynamics via PAK1.
• Offers insights into basic calcium signaling mechanisms.
What Happens During positive regulation of store-operated calcium channel activity?
ER Calcium Depletion and STIM1 Activation
In simple terms: When calcium stores in the ER run low, a sensor protein called STIM1 detects this and gets ready to open calcium channels.
Upon depletion of ER calcium stores, STIM1 oligomerizes and translocates to ER-plasma membrane junctions, where it interacts with ORAI1 channels to trigger calcium influx [1,2]. Positive regulators such as TSPAN18 protect STIM1 from ubiquitination and degradation, thereby enhancing its availability for activation.
ORAI1 Channel Gating and Calcium Influx
In simple terms: STIM1 then activates ORAI1 channels on the cell surface, allowing calcium to flow into the cell.
STIM1 directly binds to ORAI1, inducing conformational changes that open the channel pore and permit calcium entry [1,2]. This process is positively regulated by proteins like CLCA2, which promotes SOCE and modulates TMEM16A activity.
Modulation by Accessory Proteins
In simple terms: Other proteins can boost or stabilize the channel complex to keep calcium flowing.
TSPAN18 facilitates bone metastasis of prostate cancer by protecting STIM1 from TRIM32-mediated ubiquitination, thus increasing SOCE. Similarly, PAK1 modulates SOCE and nascent adhesion, linking calcium entry to cytoskeletal dynamics.
Calcium-Dependent Downstream Signaling
In simple terms: The incoming calcium triggers various cellular responses, from gene expression to immune activation.
Elevated intracellular calcium activates calcineurin/NFAT, CaMKII, and other signaling pathways that control gene expression, cell proliferation, and differentiation [4,5,8]. In central dopaminergic neurons, Orai-mediated calcium entry regulates gene expression and neuronal activity.
Key Genes Involved in GO:1901341 positive regulation of store-operated calcium channel activity
The following genes and proteins are key players in the positive regulation of store-operated calcium channel activity, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| STIM1 | ER calcium sensor that activates ORAI1 channels | Central to SOCE; target for cancer and immune disorders. |
| ORAI1 | Plasma membrane calcium channel | Mediates calcium influx; studied in neurodegeneration and immune diseases. |
| TSPAN18 | Protects STIM1 from ubiquitination, enhancing SOCE | Promotes prostate cancer bone metastasis. |
| CLCA2 | Positive regulator of SOCE and TMEM16A | Modulates calcium entry in epithelial cells. |
| PAK1 | Modulates SOCE and nascent adhesion | Links calcium signaling to cytoskeletal dynamics. |
| TRIM32 | Ubiquitinates STIM1, negatively regulating SOCE | Counteracts TSPAN18-mediated stabilization. |
| TMEM16A | Calcium-activated chloride channel | Modulated by CLCA2, affecting SOCE. |
| CaMKIIα | Calcium/calmodulin-dependent kinase | Phosphorylated during remifentanil-induced hyperalgesia. |
| NFAT | Transcription factor activated by calcium | Drives gene expression in T cells and osteoclasts. |
| Orai | Family of calcium channels | Determines dopaminergic neuron activity. |
| STIM | Family of ER calcium sensors | Includes STIM1 and STIM2; regulates SOCE. |
| Treg cells | Regulatory T cells dependent on SOCE | Eldecalcitol promotes Treg differentiation via SOCE. |
| CD4+ T cells | Immune cells with upregulated SOCE in rheumatoid arthritis | Aberrant cytokine release linked to SOCE. |
| TRPC | Transient receptor potential channels | May contribute to SOCE in some cell types. |
| Calcineurin | Calcium-dependent phosphatase | Activates NFAT; involved in immune responses. |
| SOCE complex | Multiprotein assembly at ER-PM junctions | Target for Alzheimer's disease therapy. |
| p21-activated kinase | Serine/threonine kinase | Regulates SOCE and adhesion. |
| Eldecalcitol | Vitamin D analog | Promotes Treg differentiation through SOCE. |
How Is positive regulation of store-operated calcium channel activity Regulated?
Positive regulation of store-operated calcium channel activity is itself tightly regulated by various mechanisms. TSPAN18 stabilizes STIM1 by preventing its TRIM32-mediated ubiquitination, thereby enhancing SOCE. CLCA2 positively regulates SOCE and TMEM16A, influencing calcium entry. PAK1 modulates SOCE and nascent adhesion, linking calcium signaling to cell migration. Additionally, phosphorylation of CaMKIIα contributes to remifentanil-induced hyperalgesia via SOCE. These regulatory layers ensure appropriate calcium homeostasis and are disrupted in diseases such as cancer and autoimmune disorders [1,4,7].
positive regulation of store-operated calcium channel activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TSPAN18 | Prostate cancer bone metastasis | Knockout and overexpression in prostate cancer cell lines |
| CLCA2 | Epithelial calcium transport | Knockdown and overexpression in epithelial cells |
| PAK1 | Cell adhesion and migration | Point mutation and knockout in fibroblasts |
| STIM1 | Alzheimer's disease | Knock-in and knockout in neuronal cells |
| ORAI1 | Dopaminergic neuron activity | Overexpression and knockout in neurons |
Cancer Progression and Metastasis
TSPAN18 facilitates bone metastasis of prostate cancer by protecting STIM1 from TRIM32-mediated ubiquitination, leading to enhanced SOCE and tumor progression. This highlights positive regulation of SOCE as a driver of metastatic spread.
Autoimmune and Inflammatory Diseases
In active rheumatoid arthritis, naïve CD4+ T cells exhibit upregulated SOCE and aberrant cytokine release, contributing to inflammation. Eldecalcitol ameliorates diabetic osteoporosis by promoting Treg cell differentiation through SOCE, linking calcium entry to immune regulation.
Neurodegeneration and Neurological Disorders
Store-operated calcium channel complex in postsynaptic spines is a therapeutic target for Alzheimer's disease. Orai-mediated calcium entry determines activity of central dopaminergic neurons by regulating gene expression. Remifentanil-induced postoperative hyperalgesia involves SOCE via CaMKIIα phosphorylation.
From positive regulation of store-operated calcium channel activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does TSPAN18 promote SOCE in prostate cancer? | TSPAN18 knockout and overexpression in PC-3 cells |
| How does CLCA2 regulate TMEM16A? | CLCA2 knockdown and patch-clamp in HEK293 cells |
| What is the role of PAK1 in SOCE? | PAK1 point mutants and calcium imaging |
| Can eldecalcitol enhance Treg differentiation via SOCE? | Knock-in of SOCE components in T cells |
| Does Orai mediate gene expression in dopaminergic neurons? | Orai knockout and RNA-seq in neurons |
| Is SOCE complex a target for Alzheimer's? | Knock-in mouse models and electrophysiology |
How to Study the positive regulation of store-operated calcium channel activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Calcium imaging | Intracellular calcium concentration | SOCE activity in live cells [1,2] |
| Patch-clamp | Ion channel currents | ICRAC measurement [2,5] |
| CRISPR knockout | Gene function loss | Identify positive regulators [1,4] |
| RNA-seq | Transcriptional changes | Downstream signaling |
| Co-IP/MS | Protein-protein interactions | SOCE complex composition [1,3] |
| Western blot | Protein expression and phosphorylation | STIM1 stability, CaMKIIα activation [1,8] |
| Flow cytometry | Cell phenotype and calcium flux | T cell activation [4,7] |
| Luciferase reporter | NFAT transcriptional activity | Calcium-dependent gene expression |
Calcium Imaging
Calcium imaging using fluorescent dyes (e.g., Fura-2) measures intracellular calcium changes to assess SOCE activity in live cells [1,2,3].
Electrophysiology
Patch-clamp recordings directly measure store-operated calcium currents (ICRAC) to quantify channel activity and regulation [2,5].
CRISPR Screening
Genome-wide CRISPR knockout or activation screens identify novel positive regulators of SOCE by monitoring calcium-dependent reporter expression [1,4].
Proteomics and Co-IP
Co-immunoprecipitation and mass spectrometry reveal protein interactions within the SOCE complex, such as STIM1-TSPAN18 binding [1,3].
How CRISPR Can Be Used to Study GO:1901341 positive regulation of store-operated calcium channel activity
Knockout
CRISPR knockout of positive regulators such as TSPAN18 or CLCA2 can abolish SOCE enhancement, revealing their necessity in calcium signaling and disease models [1,2].
Point Mutation
Introducing point mutations in STIM1 or ORAI1 can dissect specific domains required for positive regulation, such as ubiquitination sites or gating residues [1,3].
Knock-in
Knock-in of tagged STIM1 or ORAI1 allows live-cell imaging and proteomic analysis of SOCE complex dynamics under positive regulation [1,5].
Overexpression
Overexpression of TSPAN18 or CLCA2 enhances SOCE and can drive phenotypes like cancer metastasis or altered immune responses, validating their positive regulatory roles [1,2,4].
How EDITGENE Supports positive regulation of store-operated calcium channel activity Research
Researchers studying positive regulation of store-operated calcium channel activity-related genes often need to determine whether a candidate gene is causally involved in SOCE enhancement or is merely correlated with calcium signaling changes. EDITGENE provides comprehensive CRISPR-based services to address these questions with precision and scale.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of store-operated calcium channel activity research.
Frequently Asked Questions About positive regulation of store-operated calcium channel activity
What is GO:1901341?
GO:1901341 is a Gene Ontology term for any process that activates or increases the frequency, rate or extent of store-operated calcium channel activity [1,2].
What genes are involved in positive regulation of store-operated calcium channel activity?
Key genes include STIM1, ORAI1, TSPAN18, CLCA2, and PAK1, among others [1,2,3].
How is store-operated calcium entry positively regulated?
Positive regulation occurs through proteins like TSPAN18 that stabilize STIM1, or CLCA2 that enhances ORAI1 activity [1,2].
What diseases are associated with dysregulated SOCE?
Diseases include prostate cancer bone metastasis, rheumatoid arthritis, Alzheimer's disease, and diabetic osteoporosis [1,4,6,7].
What methods study positive regulation of SOCE?
Calcium imaging, patch-clamp, CRISPR screens, and proteomics are commonly used [1,2,3,4,5].
Can CRISPR be used to study SOCE regulators?
Yes, CRISPR knockout, knock-in, and overexpression models are powerful tools for dissecting SOCE regulation [1,2,3,4].
What is the role of TSPAN18 in SOCE?
TSPAN18 protects STIM1 from ubiquitination, thereby enhancing SOCE and promoting prostate cancer bone metastasis.
How does CLCA2 regulate calcium channels?
CLCA2 positively regulates SOCE and modulates TMEM16A activity.
Is SOCE involved in neuronal function?
Yes, Orai-mediated calcium entry regulates gene expression in dopaminergic neurons and is implicated in Alzheimer's disease [5,6].
What experimental models are used for SOCE research?
Knockout, point mutation, knock-in, and overexpression cell lines, as well as animal models, are used [1,2,3,4,5,6,7,8].
Conclusion
GO:1901341, positive regulation of store-operated calcium channel activity, is a critical biological process that fine-tunes calcium signaling in health and disease. Key regulators such as TSPAN18, CLCA2, and PAK1 modulate SOCE to influence cancer progression, immune responses, and neuronal activity [1,2,3,4,5,6,7,8]. Understanding these mechanisms offers promising avenues for therapeutic intervention. EDITGENE provides advanced CRISPR solutions to accelerate research on this pathway.
References
- 1. Zhou Q et al.. 2023. TSPAN18 facilitates bone metastasis of prostate cancer by protecting STIM1 from TRIM32-mediated ubiquitination.. J Exp Clin Cancer Res 42(1):195 PMID: 37542345
- 2. Sharma A et al.. 2018. CLCA2 is a positive regulator of store-operated calcium entry and TMEM16A.. PLoS One 13(5):e0196512 PMID: 29758025
- 3. Jeon IS et al.. 2018. Modulation of store-operated calcium entry and nascent adhesion by p21-activated kinase 1.. Exp Mol Med 50(5):1-10 PMID: 29780159
- 4. Jiang Y et al.. 2024. Eldecalcitol ameliorates diabetic osteoporosis and glucolipid metabolic disorder by promoting Treg cell differentiation through SOCE.. Cell Mol Life Sci 81(1):423 PMID: 39367914
- 5. Mitra R et al.. 2024. Orai-mediated calcium entry determines activity of central dopaminergic neurons by regulation of gene expression.. Elife 12 PMID: 38289659
- 6. Zhang H et al.. 2016. Store-Operated Calcium Channel Complex in Postsynaptic Spines: A New Therapeutic Target for Alzheimer's Disease Treatment.. J Neurosci 36(47):11837-11850 PMID: 27881772
- 7. Liu S et al.. 2014. Upregulation of store-operated Ca(2+) entry in the naïve CD4(+) T cells with aberrant cytokine releasing in active rheumatoid arthritis.. Immunol Cell Biol 92(9):752-60 PMID: 24935456
- 8. Zhou Z et al.. 2021. Store-Operated Calcium Channels Contribute to Remifentanil-Induced Postoperative Hyperalgesia via Phosphorylation of CaMKIIα in Rats.. J Pain Res 14:3289-3299 PMID: 34703304
