Nitric oxide (NO) is a signaling molecule that has capin the immune system in work by DeGroote and Fang tured our imagination. According to the common view,(DeGroote et al., 1996). These researchers found that NO diffuses over a large sphere of influence, moving bacterial virulence is conferred by a gene that protects freely through membranes of target cells to raise levels against the lethal effects of SNOs produced by the (muof cGMP. In the brain, NO influences synaptic plasticity, rine) host, whereas NO is harmless against the same apoptosis, neuronal development, and even complex bacteria. Molecular recognition of the SNO onslaught behavioral responses. This image has been reinforced and the activation of bacterial resistance is achieved by by observations in the cardiovascular and immune sys-S-nitrosylation of proteins involved in defense (Hauslatems, for example, the relaxation of blood vessels by den et al., 1996). Thus, in this system, S-nitrosylation is cGMP, and the killing of tumor cells and bacteria by the the signal and the regulator of the response. macrophage NO synthase (NOS). A similar NO signal is used by mammalian cells. Images can also be misleading. First, a wide sphere For example, the endothelium-derived relaxation factor of NO diffusion implies that it travels down concentration(EDRF)/NO-mediated relaxation of blood vessels occurs gradients that are established by extracellular sinks partly by direct activation of a potassium channel (Lancaster, 1994; Stamler, 1996). The problem with this through reactions of EDRF with critical thiols (Bolotina picture is that NO cannot achieve local action: it would et al., 1994). Likewise in the heart, SNO and peroxynitrite be leaving cells more rapidly than it reacts within. Sec-(OONO) directly activate calcium channels by a redox ond, we have come to appreciate that many NO signals mechanism that opposes the effects of cGMP (Campbell are cGMP independent. These pathways, typically et al., 1996). Ion channel activation may also account grouped under the broad heading of “redox”, have not for NO/SNO-mediated relaxations of third to fourth order been incorporated into the theory of NO action in the human airways (Gaston et al., 1994) and canine (Koh et nervous system. However, redox-related NO signals can al., 1995) or rat proximal colon (Takeuchi et al., 1996); be well-regulated posttranslational modifications that these reactions seem to be entirely independent of a rise in cGMP. Taken together, these studies emphasize are part of cellular control mechanisms. Here, we con-1) that some NO-related responses are cGMP depensider the molecular basis of NO transport and regulation dent, but many others are not; 2) increases in cGMP are in vivo, provide mechanistic insights into the specificity not synonymous with cause and effect; and 3) involveof NO-related signals, and identify a consensus motif in ment of cGMP does not preclude an additional mechaproteins for NO-related modifications. nism of NO signaling in a pathway.