were activated—a check on cause and effect that confirmed the researchers' hunch.) As another piece of evidence, these great increases in cyclic GMP production all took place within a few seconds. This was a remarkably swift reaction, well within the time frame of some of the more brisk neurotransmitters. It appears that the nitric oxide-forming enzyme is switched on as soon as the calcium channels open, and it begins at once to produce nitric oxide at full speed, with some help from calmodulin, a calcium-binding protein.

Thus, nitric oxide is indeed at work in the brain, and it is associated with one of the most important excitatory neurotransmitters—glutamate. Intriguingly, nitric oxide is neither a transmitter nor a second messenger but truly a different type of messenger between cells. By mapping the areas of the brain where the nitric oxide–forming enzyme tends to concentrate, investigators are beginning to understand more about the action of this substance.

Nitric oxide–forming enzyme is found in high concentrations in the cerebellum, which is largely involved in movement, and in the olfactory bulb; it also appears in the pituitary gland (the producer of many hormones), in sections of the eye, and in the intestine (where it may turn out to be the primary agent of muscle relaxation). One of the most exciting of recent results is the finding that certain arteries in the brain contain the enzyme not only in their interior lining but, more unusually, in the neurons that supply the outer layer—the very arteries and nerves recently shown to be involved in migraine headaches. These observations are already being applied in the rapid development of drugs to act at this site in the nitric oxide system, and may soon bring millions of migraine sufferers a new prospect of relief. This novel form of molecular signal, discovered so recently, suggests that there are still more intriguing trails to be explored within the messenger systems.

ACKNOWLEDGMENTS

Chapter 5 is based on presentations by Lily Yeh Jan, Robert Lefkowitz, and Solomon H. Snyder.



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