Postsynaptic density protein 95 (PSD-95) (PSD-95)

Postsynaptic density protein 95 (PSD-95), also known as Disks large homolog 4 (DLG4), is a major scaffolding protein in the excitatory postsynaptic density of neurons (UniProt: P78352). It belongs to the membrane-associated guanylate kinase (MAGUK) family and contains three PDZ domains that facilitate protein-protein interactions. The PDZ2 domain is of particular therapeutic interest because it anchors the N-methyl-D-aspartate (NMDA) receptor GluN2B subunit and neuronal nitric oxide synthase (nNOS) in close proximity (PubMed: 12193640). During an ischemic stroke, this arrangement allows for excessive calcium influx through NMDA receptors to trigger toxic levels of nitric oxide production, leading to neuronal death (PubMed: 32070444). Drugs like Nerinetide (NA-1) are designed to bind to the PDZ2 domain or mimic the NMDA receptor's binding motif to disrupt this interaction, thereby providing neuroprotection without blocking essential synaptic transmission (The Lancet, 2020). Beyond stroke, PSD-95 is involved in synaptic plasticity and has been linked to conditions such as neuropathic pain, Alzheimer's disease, and schizophrenia (PubMed: 28935615).

Other names

Disks large homolog 4DLG4SAP-90Synapse-associated protein 90PSD95

Inhibition of protein-protein interaction (PPI) between the PSD-95 PDZ2 domain and the NMDA receptor GluN2B subunit or nNOS.