Postsynaptic density protein 95 (PSD-95) PDZ1 domain (PSD-95 PDZ1)

Postsynaptic density protein 95 (PSD-95), also known as Disks large homolog 4 (DLG4), is a major scaffolding protein essential for the organization and functional integrity of the postsynaptic density in excitatory synapses (UniProt P78352). The PDZ1 domain of PSD-95, often acting in tandem with the PDZ2 domain, is responsible for anchoring N-methyl-D-aspartate (NMDA) receptors and neuronal nitric oxide synthase (nNOS) in close physical proximity (PubMed: 20813961). This spatial coupling allows NMDA receptor-mediated calcium influx to efficiently activate nNOS, a process that becomes pathological during ischemic stroke, leading to excessive nitric oxide production and subsequent neuronal death (PubMed: 12431388). Drugs targeting the PDZ1 domain, such as the peptide nerinetide (NA-1), aim to disrupt the interaction between PSD-95 and the NMDA receptor GluN2B subunit. This uncouples the receptor from downstream toxic signaling pathways without blocking the essential ion channel function of the NMDA receptor itself (PubMed: 22383813). This neuroprotective strategy has been extensively studied in clinical trials for acute ischemic stroke and shows promise for treating other conditions characterized by excitotoxicity, such as chronic pain and traumatic brain injury (The Lancet, 2020; PubMed: 25108915).

Other names

DLG4 PDZ1 domainDisks large homolog 4 PDZ1 domainSAP-90 PDZ1 domainSynapse-associated protein 90 PDZ1 domainPSD95 PDZ1

Inhibition of protein-protein interaction (PPI) between the PSD-95 PDZ1/2 domains and the C-terminal tail of the NMDA receptor GluN2B subunit to uncouple the receptor from neuronal nitric oxide synthase (nNOS) mediated excitotoxicity.