Department of Physiology, University of California at San Francisco School of Medicine, 513 Parnassus Avenue, San Francisco, California, CA 94143-0444, USA
* Author for correspondence (e-mail: bredt{at}itsa.ucsf.edu)
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Introduction |
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Neuronal nNOS |
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This membrane-localized nNOS complex is further linked to cytoplasmic signal transduction pathways via the physical interaction of nNOS with DexRas 1 and the adapter protein CAPON (Fang et al., 2000), which might activate a downstream MAP kinase cascade and modulate nuclear transcription. Functionally, nNOS might also represent a central component that regulates synaptic transmission and intercellular signaling, through negative regulation of the NMDAR by S-nitrosylation (Kim et al., 1999
) and NO-dependent activation of DexRas (Fang et al., 2000
). Additionally, the half-life of neuronal nNOSa protein is regulated by the Ca2+ sensitive protease calpain (Hajimohammadreza et al., 1997
).
Whereas the small quantities of NO formed during synaptic transmission modulate neuronal signaling, excess NO mediates neurotoxicity in pathological situations, such as an ischemic stroke (Huang et al., 1994). This NO toxicity is accentuated in the presence of oxidative radicals such as O2, which can also be generated by nNOS (Pou et al., 1992
). Interestingly, nNOS-expressing neurons are spared from injury associated with elevated NO, which might partly be because of the physical association of nNOS with phosphofructokinase-M (PFK), the rate-limiting enzyme in glycolysis (Firestein and Bredt, 1999
). Consequently, while therapeutic modulation of nNOS represents a potentially important approach in the setting of several clinically important neurological diseases, the balance between positive and negative effects of nNOS derived NO in the brain are complex and must be carefully weighed.
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Skeletal muscle nNOSm |
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Cardiac Muscle nNOSµ |
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Smooth muscle nNOS |
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Acknowledgments |
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References |
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