8.A.24.1.3
Na⁺/H⁺ exchange regulatory factor (NHERF) or discs large homologue 4, PSD-95, PSD95, Dig4, Digh4 of 724 aas and 0 TMSs. Acts to stabilize and organize membrane targeting of multiple transmembrane proteins, including many clinically relevant drug transporters. These PDZ proteins are normally abundant at apical membranes, where they tether membrane-delimited transporters. NHERF expression is particularly high at the apical membrane in polarized tissue such as intestinal, hepatic, and renal epithelial tissues (Walsh et al. 2015). DLG4 or PSD95 interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels and is required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. Moreover, DLG4 may reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. It also regulates the intracellular trafficking of ADR1B and controls AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density, keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression.  This involves palmitoylation (Jeyifous et al. 2016). Stargazin in complex with PSD-95 or PSD-95-assembled postsynaptic complexes forms highly concentrated and dynamic condensates via phase separation, reminiscent of stargazin/PSD-95-mediated AMPAR synaptic clustering and trapping (Zeng et al. 2019). AMPA receptor (AMPAR) trafficking in long-term potentiation (LTP) of excitatory synaptic transmission is well established. PSD-95 captures AMPARs via an interaction with the AMPAR auxiliary subunits-transmembrane AMPAR regulatory proteins (TARPs). The TARP/PSD-95 complex is an essential interaction underlying AMPAR trafficking and LTP (Ravi et al. 2022).