Appreciation of the role of nitric oxide (NO) in mammalian cell biology has toppled the paradigm that biological signaling is initiated exclusively by noncovalent, lock-and-key-type interactions with receptor proteins. Remarkably, nitric oxide is a free radical that signals by chemical reaction with its protein targets, resulting in covalent modifications and a stable alteration in protein structure and function. Although most proteins may be coerced to react with NO in vitro, the specific proteins that are functionally modified by NO within cells will depend on the concentration of NO and the composition of the intracellular milieu. A further level of complexity is introduced into NO signaling by the fact that reactions can occur with NO directly, or secondarily with NO-derived species. Much to the surprise of those who thought that reactive molecules are generated and act only under pathophysiological conditions (e.g., ischemia-reperfusion injury), NO has emerged as a prototype molecule that signals by chemistry in normal physiology. The unique attributes and importance of NO were recently recognized by the Nobel Prize Committee, with their decision to award the 1998 Prize in Medicine to Drs Furchgott, Ignarro, and Murad, pioneers in NO biology. This review surveys what we believe to be the most important mechanisms and targets of signaling by NO.
