| DLG4 |
|---|
| Gene | [DLG4](/genes/dlg4) |
| UniProt ID | [P78352](https://www.uniprot.org/uniprot/P78352) |
| Molecular Weight | 95 kDa |
| Subcellular Localization | Postsynaptic density, excitatory synapses |
| Protein Family | PSD95 family, MAGUK family |
DLG4 (Discs Large Homolog 4), more commonly known as PSD-95, is a core scaffold protein of the postsynaptic density that organizes excitatory synapses. The DLG4 gene encodes a 724-amino acid protein essential for synaptic structure, function, and plasticity.
PSD-95 contains multiple protein-interaction domains:
| Domain |
Position |
Function |
| PDZ domains (3) |
N-terminal |
Bind C-terminal motifs of receptors/ion channels |
| SH3 domain |
Middle |
Protein-protein interactions |
| GK domain |
C-terminal |
Bind guanylate kinase-associated proteins |
This modular architecture allows PSD-95 to assemble large signaling complexes at synapses.
PSD-95 organizes the postsynaptic density:
- AMPA receptor anchoring: Regulates synaptic AMPA receptor trafficking
- NMDA receptor complex: Links NMDA receptors to downstream signaling
- K+ channel regulation: Associates with Kv1 channels
- Signaling complex assembly: Recruits enzymes and effectors
PSD-95 is critical for learning and memory:
- Regulates long-term potentiation (LTP)
- Controls long-term depression (LTD)
- Modulates spine morphology
- Activity-dependent modifications
Key PSD-95 interacting proteins:
- GluA1-4: AMPA receptor subunits
- NR1, NR2A/B: NMDA receptor subunits
- AKAP79/150: A-kinase anchoring proteins
- SynGAP: Ras GTPase-activating protein
- nNOS: Neuronal nitric oxide synthase
PSD-95 alterations contribute to synaptic failure in AD:
- Synaptic loss: Reduced PSD-95 expression in AD brain
- Aβ toxicity: Amyloid-beta disrupts PSD-95 interactions
- Tau pathology: Phosphorylated tau affects PSD-95 function
- Memory deficits: Impaired synaptic plasticity
- Dopaminergic synapses: PSD-95 in striatal medium spiny neurons
- Excitotoxicity: NMDA receptor dysregulation
- Synaptic pruning: Altered PSD-95 in disease models
Targeting PSD-95 interactions shows promise:
- Neuroprotective peptides: Mimetic peptides preserving synapses
- Small molecule modulators: Stabilize PSD-95 interactions
- Gene therapy: Restore PSD-95 expression
DLG4 polymorphisms have been linked to:
- Schizophrenia
- Autism spectrum disorders
- Intellectual disability
- neurodegenerative disease progression
DLG4/PSD-95 changes in neurological disorders:
- Reduced PSD-95 levels in AD hippocampus
- Loss of dendritic spines
- Impaired synaptic transmission
- Correlation with cognitive decline
- Altered striatal PSD-95
- Dysregulated NMDA receptor signaling
- Excitotoxicity vulnerability
Targeting PSD-95:
- Peptide mimetics: Cell-permeable PSD-95 inhibitors
- Gene therapy: Viral vector delivery
- Small molecules: Stabilizing PSD-95 interactions
- Dlg4 knockout mice: Lethal phenotypes
- Transgenic models: Overexpression studies
- Conditional knockouts: Brain-specific deletion
DLG4 splice variants:
- PSD-95 alpha: Full-length isoform
- PSD-95 beta: Missing N-terminal PDZ domain
- PSD-95 gamma: Alternative C-terminus
- Developmental regulation: Isoform switching