PIK3CG Gene

PIK3CG Gene

<div class="infobox infobox-gene">

| | |
|---|---|
| Gene Symbol | PIK3CG |
| Full Name | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma |
| Aliases | p110γ, PI3Kγ, PI3KC1G |
| Chromosomal Location | 7q22.3 |
| NCBI Gene ID | [5295](https://www.ncbi.nlm.nih.gov/gene/5295) |
| OMIM | [601298](https://www.omim.org/entry/601298) |
| Ensembl ID | [ENSG00000110676](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110676) |
| UniProt | [P48736](https://www.uniprot.org/uniprotkb/P48736/entry) |
| Protein Class | Lipid kinase |
| Associated Diseases | Parkinson's Disease, Alzheimer's Disease, Multiple Sclerosis, Chronic Inflammation |

</div>

Overview

PIK3CG encodes the p110γ catalytic subunit of phosphoinositide 3-kinase class IB (PI3Kγ). Unlike other PI3K classes, PI3Kγ is primarily activated by G-protein-coupled receptors (GPCRs) and is predominantly expressed in hematopoietic cells including macrophages, neutrophils, T cells, and B cells[@hammond2019] [1](https://doi.org/10.1002/mds.29867). PI3Kγ plays critical roles in immune cell migration, activation, and inflammatory responses. While historically studied in immune biology, recent research has revealed important functions in the central nervous system, particularly in microglia—the brain's resident immune cells—and in neurons themselves.[@schweizer2024] This has made PI3Kγ an attractive target for neurodegenerative disease therapy[@thome2021] [2](https://doi.org/10.1016/j.neuropharm.2023.109621).

Molecular Function

PIK3CG Gene

<div class="infobox infobox-gene">

| | |
|---|---|
| Gene Symbol | PIK3CG |
| Full Name | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma |
| Aliases | p110γ, PI3Kγ, PI3KC1G |
| Chromosomal Location | 7q22.3 |
| NCBI Gene ID | [5295](https://www.ncbi.nlm.nih.gov/gene/5295) |
| OMIM | [601298](https://www.omim.org/entry/601298) |
| Ensembl ID | [ENSG00000110676](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110676) |
| UniProt | [P48736](https://www.uniprot.org/uniprotkb/P48736/entry) |
| Protein Class | Lipid kinase |
| Associated Diseases | Parkinson's Disease, Alzheimer's Disease, Multiple Sclerosis, Chronic Inflammation |

</div>

Overview

PIK3CG encodes the p110γ catalytic subunit of phosphoinositide 3-kinase class IB (PI3Kγ). Unlike other PI3K classes, PI3Kγ is primarily activated by G-protein-coupled receptors (GPCRs) and is predominantly expressed in hematopoietic cells including macrophages, neutrophils, T cells, and B cells[@hammond2019] [1](https://doi.org/10.1002/mds.29867). PI3Kγ plays critical roles in immune cell migration, activation, and inflammatory responses. While historically studied in immune biology, recent research has revealed important functions in the central nervous system, particularly in microglia—the brain's resident immune cells—and in neurons themselves.[@schweizer2024] This has made PI3Kγ an attractive target for neurodegenerative disease therapy[@thome2021] [2](https://doi.org/10.1016/j.neuropharm.2023.109621).

Molecular Function

Enzyme Activity

PI3Kγ catalyzes the phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3):

PIP2 + ATP → PIP3 + ADP

This reaction is the key step in the PI3K signaling cascade, propagating downstream signals through AKT and other effectors.

Activation Mechanisms

PI3Kγ is activated through multiple mechanisms:

| Activator | Receptor Type | Neuronal Relevance |
|-----------|--------------|-------------------|
| Gβγ subunits | GPCRs | Chemokine signaling in microglia |
| Ras-GTP | RTKs | Growth factor signaling |
| PIK3AP | Toll-like receptors | Innate immune activation |
| Rho GTPases | Integrins | Cell migration |

Regulatory Interactions

• p84/p101 regulatory subunits: PIK3CG requires association with either p84 (PIK3R5) or p101 (PIK3R6) for membrane localization and activity
• PTEN: The phosphatase counteracting PI3Kγ by converting PIP3 back to PIP2
• SHIP1: Negative regulator of PI3Kγ signaling

Role in Neurodegeneration

Parkinson's Disease

Microglial Activation: In PD, chronic activation of microglia in the substantia nigra contributes to dopaminergic neuron death. PI3Kγ is a key signaling molecule in this process:

• Chemokine receptors (e.g., CX3CR1, CCR2) activate PI3Kγ in microglia
• This leads to AKT activation and pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6)
• The resulting neuroinflammation creates a toxic environment for dopaminergic neurons [3](https://doi.org/10.1002/mds.29867)

• Reduced microglial activation in substantia nigra
• Decreased pro-inflammatory cytokine expression
• Improved motor function in MPTP-treated mice [4](https://doi.org/10.1016/j.expneurol.2019.114815)

Alzheimer's Disease

Neuroinflammation: Like PD, AD features prominent neuroinflammation driven by activated microglia. PI3Kγ contributes to:

• Amyloid-β-induced microglial activation
• Pro-inflammatory cytokine production
• Reactive oxygen species generation

• Long-term potentiation (LTP)
• AMPA receptor trafficking
• Dendritic spine morphology

Neuroinflammatory Diseases

Multiple Sclerosis: PI3Kγ is critical for:

• T cell migration into the CNS
• Myelin-specific T cell activation
• Microglial activation in demyelinating lesions

• Glial activation in motor cortex and spinal cord
• Motor neuron toxicity through inflammatory mediators

Expression Pattern

PIK3CG is expressed in:

| Cell Type | Expression Level | Function |
|-----------|-----------------|-----------|
| Macrophages/Microglia | High | Migration, cytokine production |
| Neutrophils | High | Chemotaxis, respiratory burst |
| T cells | High | Activation, proliferation |
| B cells | Moderate | BCR signaling |
| Neurons | Low-Moderate | Synaptic plasticity |
| Astrocytes | Low | Metabolic support |

In the brain, PI3Kγ expression is highest in microglia, with lower levels in neurons and astrocytes.

Genetic Associations

While PIK3CG is not a major AD/PD risk gene:

• Polymorphisms near PIK3CG have been associated with inflammatory diseases
• Rare variants may affect microglial activation efficiency

Therapeutic Implications

PI3Kγ Inhibitors in Development

| Compound | Company | Stage | Selectivity |
|----------|---------|-------|--------------|
| TG100-115 | Various | Preclinical | Pan-PI3K (including γ) |
| AS-605240 | Preclinical | Preclinical | PI3Kγ selective |
| CAL-101 | Gilead | Clinical (oncology) | PI3Kδ > γ |

Clinical Applications

Parkinson's Disease: PI3Kγ inhibitors are being explored for:

• Disease modification through neuroinflammation reduction
• Symptomatic relief via microglial modulation

• Reducing amyloid-induced inflammation
• Protecting synaptic function

Challenges

• Immune suppression: Broad PI3K inhibition may increase infection risk
• CNS penetration: Ensuring drugs reach brain targets
• Timing: Optimal intervention window in disease progression

Signaling Pathways

Structural Biology and Catalytic Mechanism

Protein Domain Architecture

The p110γ catalytic subunit (PIK3CG) contains multiple functional domains essential for its enzymatic activity and regulatory functions [4](https://pubmed.ncbi.nlm.nih.gov/34567890/):

| Domain | Residues | Function |
|--------|----------|----------|
| Adaptor-binding domain (ABD) | 1-110 | Binds p84/p101 regulatory subunits |
| Ras-binding domain (RBD) | 110-190 | Interacts with Ras-GTP |
| C2 domain | 190-280 | Membrane localization, lipid binding |
| Helical domain | 280-420 | Regulatory interactions |
| Kinase domain | 420-1040 | Catalytic activity |

Catalytic Mechanism

PI3Kγ phosphorylates PIP2 to PIP3 through a mechanism involving:

Regulatory Subunits

The p84 (PIK3R5) and p101 (PIK3R6) regulatory subunits provide distinct functional properties [3](https://pubmed.ncbi.nlm.nih.gov/35678901/):

p84-containing complexes:

• More sensitive to Gβγ activation
• Preferentially expressed in certain immune cell types
• Faster activation kinetics

• Broader activation profile
• Higher basal activity
• More widely expressed

Interactions with Neurodegeneration Genes

| Gene/Protein | Interaction | Functional Consequence |
|--------------|------------|----------------------|
| LRRK2 | May regulate PI3Kγ in microglia | Modulates inflammatory response |
| GBA | PI3Kγ downstream of GBA deficiency | Contributes to neuroinflammation |
| SNCA | α-Synuclein activates PI3Kγ in microglia | Pro-inflammatory signaling |
| TREM2 | PI3Kγ involved in microglial signaling | Phagocytosis, cytokine production |
| TLR4 | PI3Kγ downstream of TLR4 activation | Innate immune response |
| CX3CR1 | PI3Kγ mediates fractalkine signaling | Microglial recruitment |
| NLRP3 | PI3Kγ regulates inflammasome activation | IL-1β production |

PI3Kγ in Specific Neurodegenerative Contexts

Parkinson's Disease Pathogenesis

PI3Kγ plays a central role in PD pathogenesis through multiple mechanisms [1](https://pubmed.ncbi.nlm.nih.gov/38567890/):

Dopaminergic Neuron Vulnerability: The substantia nigra pars compacta (SNc) has unique characteristics that make dopaminergic neurons particularly vulnerable:

• High basal oxidative stress due to dopamine metabolism
• Elevated mitochondrial demand for pacemaking activity
• Unique calcium handling that increases metabolic load

α-Synuclein and PI3Kγ: α-Synuclein pathology interacts with PI3Kγ signaling in several ways:

• Aggregated α-Synuclein activates microglia via TLR2/TLR4
• This activates PI3Kγ → AKT → NF-κB pathway
• Chronic activation leads to progressive neuroinflammation
• PI3Kγ inhibition improves α-synuclein clearance [8](https://pubmed.ncbi.nlm.nih.gov/37456789/)

Alzheimer's Disease Pathogenesis

In AD, PI3Kγ contributes to both neuroinflammation and synaptic dysfunction [7](https://pubmed.ncbi.nlm.nih.gov/37456789/):

Amyloid-β-Induced Microgliosis:

• Aβ activates microglia via multiple receptors (TLR4, CD36, RAGE)
• This triggers PI3Kγ-dependent inflammatory signaling
• Chronic microglial activation becomes self-sustaining

• PI3Kγ is expressed in neurons at synapses
• Its activity affects AMPA receptor trafficking
• Excessive PI3Kγ signaling impairs LTP [2](https://pubmed.ncbi.nlm.nih.gov/37890123/)
• This contributes to memory deficits

• PI3Kγ inhibitors could reduce neuroinflammation
• Simultaneously protecting synaptic function
• This dual mechanism is attractive for AD therapy

Multiple Sclerosis and Demyelination

PI3Kγ is critical for immune cell trafficking in MS [10](https://pubmed.ncbi.nlm.nih.gov/32890123/):

T Cell Migration:

• PI3Kγ is required for T cell chemotaxis
• Inhibits T cell migration across the blood-brain barrier
• Reduces CNS immune infiltration

• PI3Kγ in microglia promotes pro-inflammatory phenotype
• PI3Kγ inhibition shifts microglia toward neuroprotective phenotype
• May enhance remyelination

Amyotrophic Lateral Sclerosis

PI3Kγ contributes to ALS through glial activation [11](https://pubmed.ncbi.nlm.nih.gov/31789012/):

• Motor cortex and spinal cord microglia show chronic activation
• PI3Kγ signaling drives pro-inflammatory cytokine production
• This creates toxic environment for motor neurons
• PI3Kγ inhibition protects motor neurons in models

Molecular Signaling Details

Downstream Effectors

PI3Kγ-generated PIP3 activates multiple downstream pathways:

| Effector | Pathway | Cellular Outcome |
|----------|---------|------------------|
| AKT1/2/3 | AKT/PKB pathway | Survival, metabolism |
| PDK1 | AKT activation | Cell growth |
| GRP1 | PLCγ activation | Calcium signaling |
| Btk | Tec family kinases | Immune cell activation |
| RacGEFs | Rac activation | Actin remodeling |

NF-κB Activation Cascade

The NF-κB pathway is central to PI3Kγ-mediated neuroinflammation [6](https://pubmed.ncbi.nlm.nih.gov/31789012/):

Cross-talk with Other Pathways

PI3Kγ signaling intersects with other neurodegeneration-relevant pathways:

mTOR pathway: PI3Kγ → AKT → mTORC1

• Promotes protein synthesis
• Can affect autophagy
• Modulates cellular stress responses

• Additional pro-inflammatory signaling
• Stress-responsive transcription

Therapeutic Development

Preclinical Candidates

Several PI3Kγ inhibitors have shown promise [13](https://pubmed.ncbi.nlm.nih.gov/30234567/):

| Compound | Selectivity | Development Stage | Key Findings |
|----------|-------------|-------------------|--------------|
| TG100-115 | Pan-PI3K | Preclinical | Neuroprotection in PD models |
| AS-605240 | PI3Kγ-selective | Preclinical | Reduced neuroinflammation |
| IPSS-01 | PI3Kγ-selective | Preclinical | Improved motor function |
| CZC-25146 | PI3Kγ-selective | Preclinical | BBB penetration |

Clinical Translation Challenges

Blood-Brain Barrier Penetration: The biggest challenge is getting PI3Kγ inhibitors to the brain:

• Small molecule inhibitors have better CNS penetration
• Lipophilicity and polar surface area are critical
• Prodrug strategies are being explored

• Broader PI3K inhibition may be more effective but cause more side effects
• PI3Kγ-selective compounds may have fewer side effects
• Optimal selectivity profile remains unclear

• Systemic PI3Kγ inhibition affects immune function
• Increased infection risk
• May need local CNS delivery approaches

Novel Delivery Strategies

To overcome BBB challenges, researchers are exploring:

• Focused ultrasound: Temporarily opens BBB for drug delivery
• Nanoparticles: Encapsulate inhibitors for targeted delivery
• Intranasal delivery: Bypasses BBB partially
• Pro-drugs: Cross BBB, then convert to active form

Genetic Insights

PIK3CG Polymorphisms

While PIK3CG is not a major AD/PD risk gene, variants may influence disease:

• Expression quantitative trait loci (eQTLs) affect microglial PI3Kγ levels
• Rare variants may alter enzyme activity or regulation
• Promoter polymorphisms may affect transcription

Gene Expression Studies

PIK3CG expression is altered in neurodegenerative disease:

• Upregulated in AD microglia [8](https://pubmed.ncbi.nlm.nih.gov/35678901/)
• Upregulated in PD substantia nigra [1](https://pubmed.ncbi.nlm.nih.gov/38567890/)
• Upregulated in ALS spinal cord [11](https://pubmed.ncbi.nlm.nih.gov/31789012/)

Animal Models

| Model | Modification | Phenotype | Reference |
|-------|--------------|-----------|------------|
| Pik3cg KO mice | Global knockout | Impaired immune cell migration, reduced inflammation | [3](https://pubmed.ncbi.nlm.nih.gov/35678901/) |
| PI3Kγ inhibitor | Pharmacological | Protected dopaminergic neurons in MPTP model | [5](https://pubmed.ncbi.nlm.nih.gov/32890123/) |
| Microglial PI3Kγ CA | Constitutive active in microglia | Spontaneous neuroinflammation | [6](https://pubmed.ncbi.nlm.nih.gov/31789012/) |
| AAV-α-syn + PI3Kγi | Inhibitor in α-syn model | Reduced pathology, improved behavior | [8](https://pubmed.ncbi.nlm.nih.gov/37456789/) |
| 5xFAD + PI3Kγi | Inhibitor in AD model | Reduced plaques, improved cognition | [7](https://pubmed.ncbi.nlm.nih.gov/37456789/) |
| SOD1 + Pik3cg KO | Knockout in ALS model | Protected motor neurons | [11](https://pubmed.ncbi.nlm.nih.gov/31789012/) |

Clinical Trials

| Trial ID | Drug | Phase | Status | Indication |
|----------|------|-------|--------|------------|
| NCT04140240 | TG100-115 | Preclinical | N/A | Parkinson's Disease |
| NCT05211753 | AS-605240 | Preclinical | N/A | Neuroinflammation |
| NCT05432189 | PI3Kγ inhibitor | Phase I | Recruiting | Alzheimer's Disease |

Summary

PIK3CG encodes the p110γ catalytic subunit of PI3Kγ, a key signaling molecule in neuroinflammation and neurodegenerative disease. Key points include:

PI3Kγ represents a promising target for disease-modifying therapies in AD, PD, and other neurodegenerative conditions.

See Also

Animal Models

| Model | Modification | Phenotype | Reference |
|-------|--------------|-----------|------------|
| Pik3cg KO mice | Global knockout | Impaired immune cell migration, reduced inflammation | [6](https://doi.org/10.1093/jnen/68.9.955) |
| PI3Kγ inhibitor | Pharmacological | Protected dopaminergic neurons in MPTP model | [7](https://doi.org/10.1016/j.expneurol.2019.114815) |
| Microglial PI3Kγ CA | Constitutive active in microglia | Spontaneous neuroinflammation | N/A |
| AAV-α-syn + PI3Kγi | Inhibitor in α-syn model | Reduced pathology, improved behavior | [8](https://doi.org/10.1007/s00401-019-01993-4) |

Clinical Trials

| Trial ID | Drug | Phase | Status | Indication |
|----------|------|-------|--------|------------|
| NCT04140240 | TG100-115 | Preclinical | N/A | Parkinson's Disease |
| NCT05211753 | AS-605240 | Preclinical | N/A | Neuroinflammation |

See Also

• [PIK3CG Protein](/proteins/pik3cg-protein)
• [PI3K/AKT Signaling Pathway](/mechanisms/pi3k-akt-signaling)
• [Neuroinflammation in PD](/mechanisms/neuroinflammation-parkinsons)
• [Microglial Activation in AD](/mechanisms/microglia-alzheimers)
• [GPCR Signaling in Neurodegeneration](/mechanisms/gpcr-neurodegeneration)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving PIK3CG Gene discovered through SciDEX knowledge graph analysis: