Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases.
Selective concentration and anchoring of ionotropic receptors at the synapse is essential for neuronal signaling. Little is known about the molecules that mediate receptor clustering in the CNS. With use of the yeast two-hybrid system to screen a rat brain cDNA library and by in vitro binding assays, we have identified an interaction between NMDA receptor subunits 2A and 2B (NR2A and NR2B) and three distinct members of the PSD-95/SAP90 family of membrane-associated putative guanylate kinases. The interaction is mediated by binding of the C terminus of the NMDA receptor subunits to the first two PDZ (also known as GLGF or DHR) domains of PSD-95/SAP90, an abundant synaptic protein associated with the membrane cytoskeleton. PSD-95 is also known to bind and cluster Shaker-type voltage-gated K+ channels. Similarities between the C-termini of NR2 subunits and K+ channels suggest a common C-terminal binding motif for PDZ domains. These data suggest that PDZ domains can function as modules for protein-protein interactions. Members of the PSD-95 family might serve to anchor NMDA receptors to the submembrane cytoskeleton and aid in the assembly of signal transduction complexes at postsynaptic sites.
Niethammer
M
M
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Kim
E
E
Sheng
M
M
D000818:Animals; D001923:Brain Chemistry; D002462:Cell Membrane / Q000201:enzymology; D018076:DNA, Complementary / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D015723:Gene Library; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism* / Q000648:ultrastructure; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D015003:Yeasts / Q000201:enzymology / Q000648:ultrastructure
D018076:DNA, Complementary; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases