The nitric oxide-cyclic GMP signal transduction system for intracellular and intercellular communication.

From our work and that of others, it is now quite apparent that the NO-cGMP system can function as an intracellular or intercellular signal transduction system (Murad et al., 1988, 1990; Murad, 1989a,b; Ishii et al., 1989, 1991). If a specific cell possesses both NO synthase and an isoform of guanylyl cyclase that is activatable with NO, then cGMP levels in that cell can be regulated by agents that alter NO synthase activity and NO formation (Fig. 1). NO, or a complex of NO which is liberated from the producing or donor cell, can also activate guanylyl cyclase in a neighboring or perhaps a distant cell to increase cGMP synthesis. In the latter scenario, NO or its carrier complex behaves as a paracrine substance, autacoid, or hormone. Interestingly, the liberated extracellular NO can also feed back and increase cGMP synthesis in the cell of origin. This is best demonstrated by the inhibitory effects of hemoglobin on agonist-induced cGMP accumulation in homogeneous cell culture systems where the hormone or agonist effects on cGMP are mediated by NO. Presumably, hemoglobin would not be permeable and could only trap or scavenge extracellular NO to account for its ability to decrease hormonally induced cGMP increases in homogeneous cell populations. There is no direct evidence that NO can act as an endocrine substance to increase cGMP synthesis in a distant target cell population. However, complexes or carrier states of NO that would liberate NO at a distant site could most certainly be viewed as endocrinological agents (hormones or autocoids). We suspect that appropriately designed experiments in the future will also support this role for NO as an endocrinological agent that can also function at a distance similar to classical hormones. Indeed, we believe that NO should be added to the list of agents that can function as a neurotransmitter, paracrine substance, and autacoid or hormone. It can also be viewed as an intracellular, as well as intercellular, messenger. To date, no substance has played such a diverse role in intracellular and intercellular signal transduction. Thus, NO appears to be a unique and simple molecule with diverse functions in signal transduction.