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The postsynaptic NMDA-receptor–PSD-95 signaling complex in excitatory synapses of the brain

MGH and Harvard Medical School, Howard Hughes Medical Institute (Wellman 423), Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA

Excitatory synapses of the brain use as neurotransmitter the amino acid glutamate, which is released in packets from the presynaptic terminal. The postsynaptic membrane is specialized for the reception of glutamate signals and the transduction of these signals into the postsynaptic cell. Containing a high concentration of glutamate receptors and associated cytoskeletal and signaling proteins, the postsynaptic specialization is visible by electron microscopy as a thickening (30 nm thick) of the postsynaptic membrane known as the postsynaptic density (PSD). The NMDA subtype of glutamate receptor (NMDAR) is an abundant constituent of the PSD and functions as a glutamate-gated calcium-permeable ion channel. NMDARs are anchored in the PSD by interactions between the cytoplasmic C-terminal tails of their NR2 subunits and the PDZ domains (orange) of PSD-95, an abundant PSD protein that forms a two-dimensional lattice immediately under the postsynaptic membrane. The PDZ domains of PSD-95 also bind to other postsynaptic membrane proteins, including potassium channels (K⁺ Ch), tyrosine kinases (ErbB4) and cell adhesion molecules (neuroligin). Having multiple domains that bind to a variety of cytoplasmic proteins, PSD-95 functions as a scaffold to assemble a specific set of signaling proteins around the NMDAR. These proteins, such as neuronal nitric oxide synthase (nNOS), SynGAP [a GTPase-activating protein (GAP) for Ras] and SPAR (a GAP for Rap), may participate in downstream signaling by NMDARs. PSD-95, in turn, interacts with GKAP and Shank, two scaffold proteins lying in the deep part of the PSD. Shank binds to Homer, which interacts directly with the cytoplasmic tail of the metabotropic glutamate receptor (mGluR), a G-protein-coupled glutamate receptor. Homer forms multimers and additionally binds to the inositol 1,4,5-trisphosphate receptor [Ins(1,4,5)P₃R] found in smooth endoplasmic reticulum (SER), thereby linking cell surface mGluRs to a downstream effector [Ins(1,4,5)P₃R] in intracellular calcium stores. Thus an extensive network of protein-protein interactions within the PSD links together different classes of postsynaptic glutamate receptor and couples them to specific intracellular signaling pathways.

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