Certain neurons possess the enzyme nitric oxide synthase (NOS), which forms NO from the amino acid arginine (see Figure). In moderate amounts, NO diffuses to adjacent neurons and provokes the formation of the second messenger cyclic guanosine monophosphate (cGMP) by activating the enzyme guanylyl cyclase. NO is not made in advance nor is it stored but seems to be made on demand and released by simple diffusion. Glutamate and calcium can trigger the formation of NO by activating NOS.^1,2

No NO Receptors

In striking contrast to classical neurotransmitters, which have numerous types and subtypes of membrane receptors on neurons, there are no NO membrane receptors.^1,2 Rather, the receptor target of NO is iron in the active site of guanylyl cyclase. Once NO binds to the iron, guanylyl cyclase is activated, and cGMP is formed. Interestingly, another component of automobile exhaust, carbon monoxide (CO), also appears to be formed by the brain and, along with NO, appears to be a key regulator of cGMP in the brain.²

The first known messenger functions for NO were described in blood vessels.^1,3 By relaxing blood vessels, NO can regulate penile erections and mediate the ability of nitroglycerin to treat cardiac angina. NO also appears to be a key regulator of blood pressure, platelet aggregation, and peristalsis.^1,2

The neurotransmitter functions of NO in the CNS have been sought ever since its synthesis in the brain was demonstrated. Speculation on its functions exists; however, the exact function of NO in the brain remains somewhat elusive. For example, NO appears to be a presynaptic neurotransmitter in the cerebellum, acting on Purkinje cells.⁴ Another proposal is that NO is the long sought-after “retrograde neurotransmitter.”⁴ Since presynaptic neurotransmitters have long been known to activate postsynaptic receptors, it seems logical that communication in this direction should be accompanied by some form of back-talk from the postsynaptic site to the presynaptic neuron. The idea is that NO is formed postsynaptically in some synapses when postsynaptic activation is prompted by a presynaptic neurotransmitter. It then diffuses back to the presynaptic neuron, carrying information in reverse.

Yes, NO Neurotoxicity

We have long known that NO is responsible for the tumoricidal and bactericidal actions of macrophages.^1-3,5; that is, the killing potential of macrophages is activated when they form NO. Large amounts of NO can “nuke” bacteria and tumor cells when the free radicals generated by NO rip them apart.

In neurons, a bit of NO leads to neuronal communication when guanylyl cyclase is activated to form the second messenger cGMP. However, when a lot of NO is formed in neurons, it can tear apart neurons just like it does bacteria and tumor cells. Excessive NO is hypothetically formed during ischemia and stroke, leading to lethal levels and neuronal destruction.⁶ New therapeutics aimed at preventing excess NO formation may prove to be effective treatments for stroke.^1-4