i.b.
The discovery of nitric oxide (NO)1 as a uniquely diffusible and reactive
molecular messenger in the vascular and immune systems motivated searches for
NO
biosynthesis throughout the body. NO was soon found in abundance in the
central and peripheral nervous systems (1). Indeed, NO synthase (NOS), the
enzyme
that produces NO from L-arginine, occurs at higher levels in brain
than in any other tissue, which facilitated the initial isolation of an NOS
protein and cloning of an
NOS cDNA (4). Intensive studies over the past 10 yr
have determined that NO mediates diverse physiological functions associated with
neurons. In the peripheral
nervous system, NO acts much like a classical
neurotransmitter in regulating gastrointestinal motility, regional blood flow,
and neuroendocrine function. In the brain,
NO acts as a neuromodulator to
control behavioral activity, influence memory formation, and intensify responses
to painful stimuli. Furthermore, NO biosynthesis in
excitable tissues is not
restricted to neurons. Recent studies have identified skeletal muscle as a major
source for NO in the body (5, 6) where NO regulates both
metabolism and
muscle contractility.
NO biosynthesis in excitable tissues is regulated by increases in
intracellular calcium, which activate NOS through the enzyme's dependence upon
calmodulin (7).
Although small amounts of NO synthesized during neural and
skeletal muscle activity mediate physiological functions, excess NO production
can mediate tissue
injury. For example, large amounts of NO produced during
periods of cerebral ischemia mediate neuronal injury in various forms of stroke
(8). Similar
NO-mediated damage may account for neurodegeneration in other
conditions as well, including Parkinson's disease, amyotrophic lateral
sclerosis, and Huntington's
disease. NO signaling is also perturbed in
various muscle diseases, particularly in Duchenne muscular dystrophy, and these
derangements may contribute to the
disease processes (9). Therefore,
pharmacological regulation of NO synthesis offers an important strategy for
treatment of neurodegenerative and muscle diseases.
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