David S. Bredt
Global Head Neuroscience Discovery
Johnson and Johnson Pharmaceutical R&D
La Jolla, CA 92121
1995 Searle Scholar
Synaptic Regulation of Nitric OxideNitric oxide (NO) mediates diverse functions in neuronal development and plasticity. In addition to mediating aspects of neuronal signaling, NO also participates in certain forms of excitotoxic brain injury. Maintenance of physiological NO signaling in the face of this potential toxicity requires tight regulation of NOS at numerous points. Our recent work demonstrates that one level of cellular regulation involves targeting of NOS proteins to intracellular membranes.
Neuronal-type NO synthase (nNOS) is concentrated at motor endplates in skeletal muscle and at synaptic junctions in brain. We find that synaptic localization of nNOS in skeletal muscle is mediated by association of nNOS with dystrophin, the protein mutated in Duchenne muscular dystrophy. The dystrophin complex interacts with an N-terminal domain of nNOS, which contains a PDZ motif. Patients with Duchenne dystrophy, evince a selective loss of nNOS protein and catalytic activity from muscle membranes. On-going work in this area focuses on understanding the role for NO in neuromuscular development and disease associated with dystrophin.
In brain, we find that the PDZ-containing domain of nNOS associates with a family of synaptic density proteins (PSD-95 and PSD-93). Interaction of nNOS with PSD-95 appears to couple appropriate synaptic stimuli to the NO signal transduction cascade in neurons. Future studies will focus on understanding the role of the nNOS / PSD-95 complex in mediating synaptic plasticity and neurotoxicity by NO.
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