DLG4

Official Full Name

discs large MAGUK scaffold protein 4

Organism

Homo sapiens

GeneID

1742

Background

This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

MRD62; PSD95; SAP90; SAP-90;

Bio Chemical Class

Ezrin/radixin/moesin-binding phosphoprotein 50

Protein Sequence

MDCLCIVTTKKYRYQDEDTPPLEHSPAHLPNQANSPPVIVNTDTLEAPGYELQVNGTEGEMEYEEITLERGNSGLGFSIAGGTDNPHIGDDPSIFITKIIPGGAAAQDGRLRVNDSILFVNEVDVREVTHSAAVEALKEAGSIVRLYVMRRKPPAEKVMEIKLIKGPKGLGFSIAGGVGNQHIPGDNSIYVTKIIEGGAAHKDGRLQIGDKILAVNSVGLEDVMHEDAVAALKNTYDVVYLKVAKPSNAYLSDSYAPPDITTSYSQHLDNEISHSSYLGTDYPTAMTPTSPRRYSPVAKDLLGEEDIPREPRRIVIHRGSTGLGFNIVGGEDGEGIFISFILAGGPADLSGELRKGDQILSVNGVDLRNASHEQAAIALKNAGQTVTIIAQYKPEEYSRFEAKIHDLREQLMNSSLGSGTASLRSNPKRGFYIRALFDYDKTKDCGFLSQALSFRFGDVLHVIDASDEEWWQARRVHSDSETDDIGFIPSKRRVERREWSRLKAKDWGSSSGSQGREDSVLSYETVTQMEVHYARPIIILGPTKDRANDDLLSEFPDKFGSCVPHTTRPKREYEIDGRDYHFVSSREKMEKDIQAHKFIEAGQYNSHLYGTSVQSVREVAEQGKHCILDVSANAVRRLQAAHLHPIAIFIRPRSLENVLEINKRITEEQARKAFDRATKLEQEFTECFSAIVEGDSFEEIYHKVKRVIEDLSGPYIWVPARERL

Open

Disease

Cerebral ischaemia, Ischaemic/haemorrhagic stroke

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

PSD-95 (Discs Large MAGUK Scaffold Protein 4), expressed by the DLG4 gene, is a member of the membrane-associated guanylate kinases (MAGUK) family that plays an important part in synapse formation and learning. PSD-95, an essential scaffold protein of the postsynaptic density (PSD), binds directly to the tail regions of NMDA receptors (NMDAR), AMPA receptors (AMPAR), and potassium channels, assisting in the regulation of the localization and function of postsynaptic membrane proteins and thus supporting the functional maturation and stability of neural synapses.

Molecular Structure and Mechanism of PSD-95

PSD-95 is made up of three PDZ domains, an SH3 domain, and a guanylate kinase domain that does not work as an enzyme. These areas enable contact with different synapse proteins. PSD-95 connects with the NR2A and NR2B parts of the NMDA receptor through its PDZ domains. It also helps to stabilize AMPAR by binding with TARP proteins. PSD-95 is an important structure in the postsynaptic area because it interacts with ion channels, signaling proteins, and binding molecules. These interactions help regulate the transfer of signals in glutamatergic synapses.

Long-term potentiation (LTP) and long-term depression (LTD) are the main processes of neural plasticity, which support brain growth and cognitive functions. PSD-95 directly adds to these processes by keeping and controlling the distribution of NMDA and AMPA receptors in the postsynaptic density area. For example, NMDA receptors are important for learning and memory because they trigger downstream signaling pathways via calcium ion input. Research shows that not having enough or completely losing PSD-95 can greatly change where NMDA receptor subunits are located. This can lead to weak neural connections and problems with thinking and memory.

Figure 1 illustrates the complex molecular interactions of PSD-95 within the postsynaptic density (PSD) of glutamatergic synapses, highlighting both its direct and indirect binding with various macromolecules, including direct interactions with NR2-containing NMDA receptors and indirect associations with AMPARs, mGluRs, and actin polymers. Figure 1. PSD-95 interactions in the PSD. An illustration describing the molecular organization of the postsynaptic density (PSD) located in the dendritic spine of glutamatergic synapses. (Coley AA, et al., 2018)

Role of PSD-95 in Neuropsychiatric Disorders

Linked to a range of neuropsychiatric disorders, including schizophrenia (SCZ), autism spectrum disorder (ASD), and intellectual disability (ID), are mutations in the DLG4 gene and functional deficits in the PSD-95 protein. Characteristics of these diseases are abnormal synapse structure and function.

Dysfunction of NMDA receptors defines the chronic neurodevelopmental disorder known as schizophrenia. Research on PSD-95 expression levels in the prefrontal cortex of schizophrenia sufferers shows that these levels are drastically lowered, therefore compromising NMDA receptor stability and structural anomalies in postsynaptic density. Moreover, PSD-95 interacts with high-risk schizophrenia proteins such as Neuroligin and DISC1, which are needed for synapse development and axon elongation; their dysfunction might be a major contributor to the starting of the illness.

Autism spectrum disease is characterized by aberrant dendritic spine density, excessive local neuronal network connection, and poor long-range neural network activity. According to studies, copy number variants of the DLG4 gene are strongly associated with the development of autism. Furthermore, overexpression of PSD-95 may boost dendritic spine density, resulting in hyperconnectivity in local neural networks. These anatomical and functional alterations might explain the repetitive behaviors and social interaction problems seen in autistic patients.

Individuals with intellectual disabilities often have brains with lower dendritic spine density. PSD-95 is critical in dendritic spine development and function because it regulates connections with proteins linked with intellectual impairment, such as Arc and IL1RAPL1. Its functional loss may cause diminished synaptic stability, leading to cognitive and learning problems.

PSD-95 and Regulation of Neuronal Excitability

The excitability balance of neurons depends critically on the shape and operation of the postsynaptic density zone. Synaptic excitatory-to-inhibitory ratios directly relate to PSD-95 expression and location. For instance, overexpression of PSD-95 may increase excitatory synaptic input by raising AMPA receptor activity, whereas its lack may lead to excessive NMDA receptor-mediated calcium ion influx, hence causing neurotoxicity and neuronal death. For many neuropsychiatric illnesses, this excitatory imbalance might be a main pathogenic element.

Future Therapeutic Strategies: Restoring PSD-95 Function

Therapeutic options for PSD-95 impairment are emerging as a research focus. Small molecule medicines and gene therapy are two potential approaches for restoring PSD-95 expression and function in the synapse. Modulating the connection between PSD-95 and NMDA receptors, or restoring normal function of the postsynaptic density region by changing associated signaling pathways, might be useful treatments for schizophrenia and autism. Furthermore, animal studies have shown that restoring PSD-95 expression levels might restore cognitive impairments, providing fresh hope for the treatment of neuropsychiatric illnesses.

References:

Tümer Z, Dye TJ, et al. DLG4-Related Synaptopathy. 2023 Jun 22. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024.
Coley AA, Gao WJ. PSD95: A synaptic protein implicated in schizophrenia or autism? Prog Neuropsychopharmacol Biol Psychiatry. 2018 Mar 2;82:187-194.

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