INTERACTION OF NITRIC-OXIDE SYNTHASE WITH THE POSTSYNAPTIC DENSITY PROTEIN PSD-95 AND ALPHA-1-SYNTROPHIN MEDIATED BY PDZ DOMAINS

Neuronal nitric oxide synthase (nNOS) is concentrated at synaptic junc tions in brain and motor endplates in skeletal muscle. Here, we show t hat the N-terminus of nNOS, which contains a PDZ protein motif, intera cts with similar motifs in postsynaptic density-95 protein (PSD-95) an d a related novel protein, PSD-93. nNOS and PSD-95 are coexpressed in numerous neuronal populations, and a PSD-95/nNOS complex occurs in cer ebellum. PDZ domain interactions also mediate binding of nNOS to skele tal muscle syntrophin, a dystrophin-associated protein. nNOS isoforms lacking a PDZ domain, identified in nNOS(Delta/Delta) mutant mice, do not associate with PSD-95 in brain or with skeletal muscle sarcolemma. Interaction of PDZ-containing domains therefore mediates synaptic ass ociation of nNOS and may play a more general role in formation of macr omolecular signaling complexes.