2002 – Michael A. Marletta

Cellular Signaling with Nitric Oxide: A Collision Course for Chemistry and Biology?

Chance observations and serendipity have often played a prominent role in scientific discoveries. This is especially true in what has become known as the nitric oxide (NO) story. Nitric oxide is toxic and is a component of smog and cigarette smoke, but it has also been found to be made normally by animals including humans. NO is synthesized by the enzyme nitric oxide synthase which converts the amino acid L-arginine to citrulline and NO. NO functions in biology in two very important ways. First it has been found to be a messenger by which cells communicate with one another (signal transduction) and secondly has been found to play a critical role in the host response to infection. In the host response to infection, it appears that the toxic properties of NO have been harnessed by the immune system to kill or at least slow the growth of invading organisms. The non-specific chemical reactivity with key cellular targets is responsible for this action. In signaling, NO directly activates the enzyme guanylate cyclase (sGC). Once activated, sGC converts GTP to cGMP and pyrophosphate. The cGMP formed is responsible for the well-documented actions of NO such as blood vessel dilation. With the initial discovery of NO signaling, several important questions emerged that centered largely on the issue of how a signaling system functions when the signaling agent is chemically reactive (short-lived), highly diffusible, and toxic. Critical, especially in signaling, is the control of NO biosynthesis and interaction with the biological receptors at a concentration that will not harm the host. Why did nature choose NO? That question engenders only speculation. How does NO work (i.e. what does NO do and how does it do it without harm)? Answers to those questions can now be offered as an interesting picture of molecular level details emerges.