n this essay, Dr. David Bredt of the University of California, San Francisco, provides a synopsis of his research on the role of nitric oxide in the nervous system. Dr. Bredt’s work has earned him the distinction of being among the 200 most-cited scientists overall in ISI Essential Science Indicators, with 110 papers garnering 16, 397 cites to date in the fields of Neuroscience & Behavior, Biology & Biochemistry, Molecular Biology & Genetics, and Clinical Medicine, as well as in the Multidisciplinary field. Dr. Bredt is a Professor in the Department of Physiology at UCSF, and he is also affiliated with the university’s Program in Biological Sciences and the Biomedical Sciences Graduate Program. His main focus in the Department of Physiology is in Neuroscience, particularly the molecular basis of postsynaptic organization.  Read incite's Institution feature this month about the University of California, San Francisco.)

Nerve cells use neurotransmitter to communicate with each other. Classical studies have shown that neurotransmitters are amino acids, hormones, or larger peptides that are released from one nerve cell and bind to a receptor protein on the surface of a neighboring cell. However, this paradigm changed in the late 1980s when we and others discovered that nitric oxide (NO), a simple diatomic molecule, is also used as a neurotransmitter. The idea that NO could be a neurotransmitter was shocking to the neuroscience community because NO is an evanescent gas that simply diffuses across cell barriers and permeates the brain. NO also seemed an unlikely biological mediator because it is a toxic free radical—a component of air pollution. Our research over the past 12 years has been to understand how nerve cells make NO and use this potential toxin as a signaling molecule.

To help to understand how NO is formed and how the body controls this potentially toxic signal, we characterized the biosynthetic enzyme, NO synthase, which makes NO from arginine. We found that the NO synthase is regulated by calcium, which explained why the NO levels are increased in active cells. Using a series of painstaking biochemical steps, we purified the NO synthase enzyme to homogeneity from brain. The purified NO synthase protein was then used to design probes to clone the DNA for the gene that encodes NO synthase.

Once we had purified the NO synthase enzyme protein, we developed antibodies to the enzyme and localized it throughout the body. Our most dramatic observation was that NO synthase occurs almost exclusively in neurons. In the brain neurons are only 15% of all cells, with the remaining being the glial cells which provide metabolic support for neurons; yet no enzyme protein was detected in glia. Interestingly, NO synthase is not in all neurons, but in quite discrete populations. In the brain NO plays critical roles in aspect of learning and memory.

Outside of the brain, we found that NO synthase often occurs in nerve cells that are adjacent to smooth muscle. This fit with discoveries of the 1999 Nobel Laureates Dr. Robert Furchgott, Louis Ignarro, and Ferid Murad that NO is a major endogenous dilator of blood vessels. Indeed, release of NO from peripheral nerves causes a dramatic relaxation of adjacent muscles. For example, release of NO from neurons in the intestine participates in the relaxation phase of peristalsis. Also, release of NO from neurons of the pelvic plexus dilates penile blood vessels to induce penile erection. In fact, Viagra enhances erection by prolonging the actions of NO on penile blood vessels.

While small amounts of NO synthesized during neuronal activity mediate physiological functions, excess NO production can mediate tissue injury. Large amounts of NO produced during periods of cerebral ischemia mediate neuronal injury in various forms of stroke. Similar NO-mediated damage may account for neurodegeneration in other conditions including Parkinson's disease, amyotrophic lateral sclerosis (ALS), 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. Pharmacological regulation of NO synthesis offers an important strategy for treatment of neurodegenerative and muscle diseases. Our ongoing studies seek to understand physiological roles for NO and for methods to curb excess formation of this potentially toxic neurotransmitter.

David S. Bredt, M.D./Ph.D.
Department of Physiology
University of California, San Francisco
San Francisco, CA, USA

Read incite's Institution feature this month about the University of California, San Francisco.)