The initial skepticism surrounding the discoveries showing that nitric oxide (•NO) is endogenously synthesized and plays a central role in cell-to-cell signaling as well in the host response to infection has largely disappeared, although central questions in all aspects of the biological function of •NO still remain. The skepticism was based on the fact that most investigators could not envision how a molecule as toxic as •NO could function in a biological setting. As the facts have unfolded over the last decade, it has become clear that •NO functions very effectively as a cell-to-cell signaling agent.¹ The chemical properties of •NO, namely a fast diffusion rate from the site of generation, the ability to cross cellular membranes and a chemical reactivity that allows it to function without the apparent need for a complicated system that acts to terminate the signal are well-suited to the appointed task (Figure 1). Critical for function is a highly regulated •NO biosynthetic machinery as well as a very sensitive receptor that will respond to non-toxic •NO levels. It is clear now that both these entities exist.

Although the main focus of this review is the mechanism of •NO cellular signaling, it is also without question that •NO plays a crucial role in the host response to infection. In fact, it appears that the immune system has harnessed the toxic properties of •NO to induce cytostasis in invading microorganisms as well as in tumor cells. Presumably •NO acts in a non-specific fashion by interfering with the function of key metalloproteins. Ferrous iron centers are particularly susceptible to •NO-induced inhibition because •NO typically binds tightly to proteins of this type, thus interfering with their functions.

Figure 1: Mechanism of •NO Production