GO:1905664 regulation of calcium ion import across plasma membrane: Calcium Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905664 describes any process that modulates the frequency, rate or extent of calcium ion import across the plasma membrane, a critical control point for cytosolic Ca2+ signals.
• Calcium import across the plasma membrane is mediated by channels, transporters and pumps whose activity is tuned by voltage, ligands, phosphorylation and interacting proteins.
• Dysregulation of this process contributes to cardiac arrhythmias, neurodegenerative disease, cancer and infectious disease pathology.
• Key molecular players include voltage-dependent anion channel VDAC2, lysosomal TMEM165, the Mycobacterium tuberculosis PE15/PPE20 complex, and plant CAX transporters.
• CRISPR knockout, point-mutation, knock-in and overexpression models enable causal testing of candidate regulators in human cells and animal models.
• EDITGENE provides end-to-end CRISPR cell model generation and library screening to dissect calcium import regulatory networks.
Description
Calcium ions (Ca2+) are universal second messengers that control muscle contraction, secretion, gene expression and cell survival. The concentration of free Ca2+ in the cytosol is kept low at rest, and cells rapidly import Ca2+ from the extracellular space or release it from intracellular stores to shape signaling. GO:1905664, regulation of calcium ion import across plasma membrane, captures the regulatory layer that determines when, where and how much Ca2+ enters the cytosol across the plasma membrane. This term is distinct from the transport activity itself; it describes modulatory processes that change the frequency, rate or extent of Ca2+ import. Because Ca2+ import is central to excitation-contraction coupling, immune activation and neuronal plasticity, its regulators are intensely studied as drug targets and disease modifiers. Experimental work has shown that plasma membrane Ca2+ import is influenced by membrane potential, polyamines, pH and protein-protein interactions. For example, polyamines cause plasma membrane depolarization and modulate H+-ATPase activity in plant roots, indirectly affecting Ca2+ fluxes. In cardiac tissue, structural plasticity of the nuclear pore complex in response to nuclear import regulators highlights how transport regulation is integrated with cellular state. Understanding GO:1905664 therefore requires combining electrophysiology, imaging and genetic perturbation to identify the molecules that set the gain on Ca2+ entry.
regulation of calcium ion import across plasma membrane At A Glance
| GO ID | GO:1905664 |
|---|---|
| GO term | regulation of calcium ion import across plasma membrane |
| Ontology | biological_process |
| Synonym | none |
| Major function | Modulates the frequency, rate or extent of Ca2+ import across the plasma membrane |
| Related transport | Calcium ion import across plasma membrane (GO:0070588) |
| Regulatory direction | Can be positive or negative |
| Cellular context | Plasma membrane, cytosol, extracellular space |
| Example regulators | VDAC2, TMEM165, PE15/PPE20 complex, CAX1/CAX3, polyamines |
What Is GO:1905664?
GO:1905664 is a biological process term defined as any process that modulates the frequency, rate or extent of calcium ion import across the plasma membrane. In other words, it is the regulatory control of Ca2+ entry into the cell from the outside, rather than the physical translocation step itself. This regulation can be positive or negative and may involve changes in channel open probability, transporter trafficking, membrane potential or local lipid environment.
Why Is regulation of calcium ion import across plasma membrane Important in Cell Biology?
Regulation of calcium ion import across the plasma membrane is important because Ca2+ entry controls essential physiological responses such as cardiac rhythm, neurotransmitter release, immune cell activation and cell death. When this regulation fails, cells either fail to mount a Ca2+ signal or suffer Ca2+ overload, both of which are linked to disease. For researchers, GO:1905664 provides a framework to annotate genes and pathways that tune Ca2+ entry, enabling mechanistic studies and therapeutic targeting.
• Controls excitation-contraction coupling in the heart and thus cardiac rhythm.
• Sets the amplitude and duration of Ca2+ signals that drive gene expression.
• Modulates immune cell activation and pathogen-host interactions.
• Influences cell survival and death decisions through Ca2+ overload.
• Is a target for drugs used in bradyarrhythmia and other cardiovascular conditions.
• Regulates plant guard cell function and auxin transport via apoplastic pH.
• Integrates with H+-ATPase activity and membrane potential in plants.
• Provides a mechanistic entry point for understanding lysosomal ion homeostasis.
• Can be hijacked by pathogens to facilitate infection.
• Offers biomarkers and therapeutic targets in cancer and neurodegeneration.
What Happens During regulation of calcium ion import across plasma membrane?
Sensing the need for Ca2+ entry
In simple terms: The cell first detects a signal that it needs more calcium inside.
Regulation begins with sensors that detect changes in membrane potential, ligand binding or intracellular Ca2+ stores. For example, depolarization of the plasma membrane can open voltage-gated Ca2+ channels, while depletion of intracellular stores triggers store-operated Ca2+ entry. In plant roots, polyamines cause plasma membrane depolarization and modulate H+-ATPase pump activity, which in turn affects the driving force for Ca2+ import. In cardiac tissue, structural plasticity of the nuclear pore complex in response to regulators of nuclear import illustrates how transport regulation is coupled to cellular state.
Modulation of channel and transporter activity
In simple terms: Proteins that let calcium in are turned up or down.
Once a need is sensed, the activity of Ca2+ channels and transporters is adjusted. VDAC2 is a voltage-dependent anion channel with specific cellular functions that include regulation of ion fluxes. The lysosomal protein TMEM165 mediates lysosomal Ca2+ import and H+ efflux, controlling cellular ion homeostasis and survival. In Mycobacterium tuberculosis, the PE15/PPE20 complex transports calcium across the outer membrane, showing that even pathogens regulate Ca2+ import. Plant vacuolar CAX1 and CAX3 influence auxin transport in guard cells via regulation of apoplastic pH, indirectly affecting Ca2+ import.
Integration with cellular homeostasis
In simple terms: Calcium import is balanced with other ions and pH.
Regulation of Ca2+ import is not isolated; it is integrated with H+ and Na+ homeostasis. TMEM165 controls both lysosomal Ca2+ import and H+ efflux, linking Ca2+ to pH regulation. In Toxoplasma, a single Na+-Pi cotransporter plays key roles in phosphate import and control of parasite osmoregulation, illustrating how ion transport networks intersect. Polyamines modulate H+-ATPase activity in pea roots, further demonstrating cross-talk between Ca2+ import and proton gradients.
Feedback and termination of the signal
In simple terms: The cell shuts off calcium entry when the signal is done.
After Ca2+ has entered, feedback mechanisms reduce further import to prevent overload. This can involve Ca2+-dependent inactivation of channels, activation of Ca2+ pumps and exchangers, and changes in membrane potential. The structural plasticity of the cardiac nuclear pore complex in response to regulators of nuclear import suggests that nuclear transport and Ca2+ signaling are coordinated. In plants, CAX1 and CAX3 influence apoplastic pH, which can feed back on Ca2+ import.
Key Genes Involved in GO:1905664 regulation of calcium ion import across plasma membrane
The following genes and proteins have been experimentally linked to regulation of calcium ion import across the plasma membrane or to closely related ion transport processes.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VDAC2 | Voltage-dependent anion channel; regulates ion fluxes | Mitochondrial and plasma membrane ion transport |
| TMEM165 | Mediates lysosomal Ca2+ import and H+ efflux | Cellular ion homeostasis and survival |
| PE15/PPE20 | Mycobacterial complex that transports calcium | Pathogen Ca2+ import and host interaction |
| CAX1 | Vacuolar Ca2+/H+ exchanger; influences apoplastic pH | Plant guard cell auxin transport |
| CAX3 | Vacuolar Ca2+/H+ exchanger; influences apoplastic pH | Plant guard cell auxin transport |
| H+-ATPase | Proton pump; modulates membrane potential | Polyamine response in plant roots |
| Na+-Pi cotransporter | Phosphate import and osmoregulation | Toxoplasma parasite physiology |
| Nuclear pore complex proteins | Regulate nuclear import | Cardiac structural plasticity |
| Yuanjiang decoction targets | Network pharmacology targets for bradyarrhythmia | Cardiac Ca2+ regulation |
| Calcium channels (generic) | Mediate Ca2+ entry | General Ca2+ signaling |
| Calcium pumps (generic) | Extrude Ca2+ | Termination of Ca2+ signals |
| Calcium exchangers (generic) | Exchange Ca2+ for Na+ | Membrane potential regulation |
| Store-operated Ca2+ entry proteins | Respond to store depletion | Immune and cardiac function |
| Lysosomal Ca2+ transporters | Import Ca2+ into lysosomes | Lysosomal homeostasis |
| Pathogen Ca2+ transporters | Import Ca2+ for virulence | Infectious disease |
| Plant ion transporters | Regulate apoplastic pH and ion balance | Plant physiology |
| Cardiac ion channels | Control action potential and Ca2+ entry | Arrhythmia research |
How Is regulation of calcium ion import across plasma membrane Regulated?
Regulation of calcium ion import across the plasma membrane is itself regulated at multiple levels. Membrane potential, pH and polyamines can alter the driving force for Ca2+ entry. Protein-protein interactions, such as those involving VDAC2, can modulate channel activity. Lysosomal TMEM165 links Ca2+ import to H+ efflux, showing that organellar ion homeostasis feeds back on plasma membrane transport. In pathogens, the PE15/PPE20 complex is dedicated to Ca2+ transport and may be regulated by host signals. Plant CAX transporters influence apoplastic pH, which can in turn affect Ca2+ import. These layers of regulation ensure that Ca2+ signals are context-appropriate.
regulation of calcium ion import across plasma membrane and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| TMEM165 | Lysosomal ion homeostasis and survival | TMEM165 KO HeLa cells |
| PE15/PPE20 | Mycobacterial calcium transport | M. tuberculosis infection model |
| VDAC2 | Ion transport and apoptosis | VDAC2 KO mouse embryonic fibroblasts |
| CAX1/CAX3 | Plant guard cell function | Arabidopsis cax1 cax3 double mutant |
| Yuanjiang decoction targets | Bradyarrhythmia | Network pharmacology and LC-MS |
Cardiac arrhythmias
Altered regulation of Ca2+ import across the plasma membrane can disturb cardiac action potentials and contribute to bradyarrhythmia. Network pharmacology studies of Yuanjiang decoction for bradyarrhythmia have identified targets related to ion transport and Ca2+ signaling. Structural plasticity of the cardiac nuclear pore complex in response to nuclear import regulators further highlights how transport regulation is integrated with cardiac function.
Neurodegeneration and lysosomal disorders
TMEM165 controls lysosomal Ca2+ import and H+ efflux, and its dysfunction is linked to cellular ion imbalance and reduced survival. Because lysosomal Ca2+ homeostasis is critical for neuronal health, regulators of Ca2+ import may contribute to neurodegenerative mechanisms.
Infectious disease
Mycobacterium tuberculosis uses the PE15/PPE20 complex to transport calcium across its outer membrane, which is important for host-pathogen interactions. Toxoplasma relies on a Na+-Pi cotransporter for phosphate import and osmoregulation, illustrating how pathogens manipulate ion transport.
Cancer and cell survival
Ca2+ import regulation influences cell survival decisions. VDAC2-specific functions in ion transport and apoptosis have been structurally characterized. Dysregulated Ca2+ entry can promote proliferation or death depending on context, making these pathways attractive for cancer research.
From regulation of calcium ion import across plasma membrane-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of TMEM165 alter Ca2+ import? | TMEM165 knockout cell line |
| Does VDAC2 point mutation affect ion flux? | VDAC2 point-mutation knock-in |
| Can PE15/PPE20 be tagged for localization? | Tagged knock-in in mycobacteria |
| Does CAX1 overexpression change apoplastic pH? | Plant overexpression line |
| Does polyamine treatment modulate H+-ATPase? | Pea root treatment assay |
| Does Na+-Pi cotransporter knockout affect osmoregulation? | Toxoplasma knockout |
How to Study the regulation of calcium ion import across plasma membrane Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Calcium imaging | Cytosolic Ca2+ changes | Live-cell signaling |
| Patch-clamp | Ion currents | Channel regulation |
| CRISPR knockout | Loss-of-function effects | Causal gene testing |
| CRISPR knock-in | Tagged or mutant protein expression | Localization and function |
| Overexpression | Gain-of-function effects | Plant transporter studies |
| Network pharmacology | Compound-target interactions | Drug mechanism |
| LC-MS | Metabolite and compound profiling | Decoction analysis |
Calcium imaging
Fluorescent Ca2+ indicators such as Fura-2 or GCaMP are used to measure changes in cytosolic Ca2+ in live cells. This method directly reports the outcome of regulation of Ca2+ import across the plasma membrane.
Electrophysiology
Patch-clamp recordings measure currents carried by Ca2+ channels and transporters, providing kinetic details on regulation.
Genetic perturbation
CRISPR knockout, point mutation, knock-in and overexpression are used to test causality of candidate regulators.
Network pharmacology and LC-MS
These approaches identify active compounds and mechanisms, as shown for Yuanjiang decoction in bradyarrhythmia.
How CRISPR Can Be Used to Study GO:1905664 regulation of calcium ion import across plasma membrane
Knockout
CRISPR knockout of candidate regulators such as TMEM165 or VDAC2 can reveal their necessity for Ca2+ import across the plasma membrane.
Point Mutation
Point mutations can be introduced to mimic disease-associated variants or to disable specific residues in ion transporters, allowing structure-function analysis.
Knock-in
Tagged knock-in of genes like PE15/PPE20 enables visualization and biochemical isolation of the transport complex.
Overexpression
Overexpression of plant CAX transporters or mammalian channels can test gain-of-function effects on Ca2+ import and downstream physiology.
How EDITGENE Supports regulation of calcium ion import across plasma membrane Research
Researchers studying regulation of calcium ion import across plasma membrane-related genes often need to determine whether a candidate gene is causally involved in Ca2+ entry, and CRISPR-based cell models provide the most direct way to test this.
Contact EDITGENE today to design your custom CRISPR model for regulation of calcium ion import across plasma membrane research.
Frequently Asked Questions About regulation of calcium ion import across plasma membrane
What is GO:1905664?
GO:1905664 is a Gene Ontology biological process term defined as any process that modulates the frequency, rate or extent of calcium ion import across the plasma membrane.
What genes are involved in regulation of calcium ion import across plasma membrane?
Genes include TMEM165, VDAC2, PE15/PPE20, CAX1, CAX3 and various ion channels and transporters.
How is calcium ion import across the plasma membrane regulated?
It is regulated by membrane potential, pH, polyamines, protein-protein interactions and organellar feedback.
Why is regulation of calcium ion import important for disease?
Dysregulation contributes to cardiac arrhythmias, neurodegeneration, infectious disease and cancer.
What methods study regulation of calcium ion import?
Calcium imaging, patch-clamp, CRISPR perturbation, network pharmacology and LC-MS are commonly used.
What is the role of TMEM165 in calcium import?
TMEM165 mediates lysosomal Ca2+ import and H+ efflux, controlling cellular ion homeostasis and survival.
How does VDAC2 regulate calcium?
VDAC2 is a voltage-dependent anion channel with specific cellular functions in ion transport and apoptosis.
Can CRISPR be used to study calcium import regulators?
Yes, CRISPR knockout, knock-in, point mutation and overexpression are widely used to test causality.
What is the connection between calcium import and bradyarrhythmia?
Network pharmacology studies have identified ion transport and Ca2+ signaling targets relevant to bradyarrhythmia.
How do plant CAX transporters affect calcium import?
CAX1 and CAX3 influence auxin transport in guard cells via regulation of apoplastic pH, indirectly affecting Ca2+ import.
Conclusion
GO:1905664, regulation of calcium ion import across the plasma membrane, is a central node in Ca2+ signaling that integrates membrane potential, pH, protein interactions and organellar feedback. Its molecular players, from TMEM165 and VDAC2 to pathogen and plant transporters, are experimentally tractable and disease-relevant. CRISPR-based models and advanced imaging will continue to reveal how this regulation is achieved and how it can be therapeutically modulated.
References
- 1. Chen R et al.. 2025. Lysosomal TMEM165 controls cellular ion homeostasis and survival by mediating lysosomal Ca(2+) import and H(+) efflux.. Nat Commun 16(1):5209 PMID: 40473625
- 2. Boradia V et al.. 2022. The Mycobacterium tuberculosis PE15/PPE20 complex transports calcium across the outer membrane.. PLoS Biol 20(11):e3001906 PMID: 36441815
- 3. Naghdi S et al.. 2016. VDAC2-specific cellular functions and the underlying structure.. Biochim Biophys Acta 1863(10):2503-14 PMID: 27116927
- 4. Perez-Terzic C et al.. 1999. Structural plasticity of the cardiac nuclear pore complex in response to regulators of nuclear import.. Circ Res 84(11):1292-301 PMID: 10364567
- 5. Wang X et al.. 2023. Network pharmacology and LC-MS approachs to explore the active compounds and mechanisms of Yuanjiang decoction for treating bradyarrhythmia.. Comput Biol Med 152:106435 PMID: 36535207
- 6. Pottosin I et al.. 2014. Polyamines cause plasma membrane depolarization, activate Ca2+-, and modulate H+-ATPase pump activity in pea roots.. J Exp Bot 65(9):2463-72 PMID: 24723394
- 7. Asady B et al.. 2020. A single Na+-Pi cotransporter in Toxoplasma plays key roles in phosphate import and control of parasite osmoregulation.. PLoS Pathog 16(12):e1009067 PMID: 33383579
- 8. Cho D et al.. 2012. Vacuolar CAX1 and CAX3 influence auxin transport in guard cells via regulation of apoplastic pH.. Plant Physiol 160(3):1293-302 PMID: 22932758
