Chapter 168

## Abstract

Abstract

1. Modern molecular biology has revealed vast numbers of large and complex proteins and nucleic acids that regulate body function. By contrast, discoveries over the past 10 years indicate that crucial features of neuronal communication, blood vessel modulation, and immune response are mediated by a remarkably simple chemical, nitric oxide (NO).

2. Endogenous NO is generated from arginine by a family comprised of three distinct calmodulin-dependent NO synthase (NOS) enzymes. NOS from endothelial cells (eNOS) and neurons (nNOS) are both constitutively expressed enzymes, whose activities are stimulated by increases in intracellular calcium. Immune functions for NO are mediated by a calcium-independent inducible NOS (iNOS). Expression of iNOS protein requires transcriptional activation, which is mediated by specific combinations of cytokines. All three NOSs use NADPH as an electron donor and employ five enzyme cofactors to catalyze a five-electron oxidation of arginine to NO with stoichiometric formation of citrulline.

3. Highest levels of NO throughout the body are found in neurons, where NO functions as a unique messenger molecule. In the autonomic nervous system NO functions as a major nonadrenergic noncholinergic (NANC) neurotransmitter. This NANC pathway plays a particularly important role in producing relaxation of smooth muscle in the cerebral circulation and the gastrointestinal, urogenital, and respiratory tracts. Disregulation of NOS activity in autonomic nerves plays a major role in diverse pathophysiological conditions, including migraine headache, hypertrophic pyloric stenosis, and male impotence. In the brain, NO functions as a neuromodulator and appears to mediate aspects of learning and memory.

4. Although endogenous NO was originally appreciated as a mediator of smooth muscle relaxation, NO also plays a major role in skeletal muscle. Physiologically, muscle-derived NO regulates skeletal muscle contractility and exercise-induced glucose uptake. nNOS occurs at the plasma membrane of skeletal muscle, which facilitates diffusion of NO to the vasculature to regulate muscle perfusion. nNOS protein occurs in the dystrophin complex in skeletal muscle and NO may therefore participate in the pathophysiology of muscular dystrophy.

5. NO signaling in excitable tissues requires rapid and controlled delivery of NO to specific cellular targets. This tight control of NO signaling is largely regulated at the level of NO biosynthesis. Acute control of nNOS activity is mediated by allosteric enzyme regulation, by posttranslational modification, and by subcellular targeting of the enzyme. nNOS protein levels are also dynamically regulated by changes in gene transcription, which affords long-lasting changes in tissue NO levels.

6. While NO normally functions as a physiological neuronal mediator, excess production of NO mediates brain injury. Overactivation of glutamate receptors associated with cerebral ischemia and other excitotoxic processes results in massive release of NO. As a free radical, NO is inherently reactive and mediates cellular toxicity by damaging critical metabolic enzymes and by reacting with superoxide to form peroxynitrite, an even more potent oxidant. Through these mechanisms, NO appears to play a major role in the pathophysiology of stroke, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis.

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