"Just say NO" is the unspoken slogan of a growing number ofmolecular neurobiologists, immunologists, oncologists,cardiologists and other scientists exploring the power of nitricoxide.

NO, an atom each of nitrogen and oxygen, is one of the simplestmolecules known and the smallest one active in the body. Itsprotean effects on cells and tissues are only beginning to beknown.

Who would have thought four or five years ago that thiscolorless toxic gas, nitrogen monoxide, was a neurotransmitter,the first such gaseous messenger ever discovered? NO was soonfound in tissues throughout the body, from blood vessels toliver cells, from inflammation to malignancy. Nitric oxide issynthesized in cells from the amino acid arginine. Its half-lifein the body is about five seconds.

Today's issue of Nature shrinks the envelope of uncertaintyabout NO another notch with a paper titled "Amplification ofcalcium-induced gene transcription by nitric oxide in neuronalcells." Its principal author is a Russian molecular neurobiologist,Grigori Enikolopov, on long-term loan from Moscow's Instituteof Molecular Biology to the Cold Spring Harbor Laboratory.

In an intricate experiment, he and his co-author/spouse,Natalia Peunova, determined, as Enikolopov told BioWorld, that"if a nitric oxide signal in a cell is combined with a very weakcalcium signal, the NO can amplify the calcium ion's messageinto a strong signal, mediating for example transcription.

He presumes that because calcium molecules are ubiquitous,and key messengers in all cells, the gaseous hormone NOapparently potentiates weak calcium signals, which dictatehousekeeping cellular decisions about everyday physiology,from growth and differentiation to synapse formation andelectric impulse propagation.

Circa 1990, Salvador Moncada of Wellcome ResearchLaboratories in Britain revealed the effects of NO on thecardiovascular system. Michael Marletta of the University ofMichigan elucidated NO's action on macrophages. And SolomonSnyder, who heads the neuroscience department at JohnsHopkins University, discovered NO's co-signaling role in thebrain and nervous system as the first gaseousneurotransmitter.

Working with Solomon, neurophysiologist David Bredt purifiedand cloned the gene for NO synthase, the enzyme thatunleashes the gaseous messenger in the brain. Bredt toldBioWorld that Enikolopov's paper in Nature is "exciting. A verysignificant finding of this new class of gaseousneurotransmitters, whose functions remain unclear."

Bredt added pointedly that "NO seems to be involved inlearning and memory, and this paper is a strong step in thatdirection." He explained that NO is synthesized in a number ofcerebral centers, including the hippocampus, where memoryand learning arise. Because they leave long-lasting traces, thesemental effects "do not require synthesis of new proteins. Thispaper is the first example of the generation of such pathways."

On this score, Enikolopov said: "When thinking about learningor memory, or wound healing, or angiogenesis, or stroke andpost-stroke events in the brain, as soon as you're talking aboutsuch long-term changes rather than one second -- for example,a heart beat -- then you immediately start thinking about geneexpression.

"These cells are not only getting a signal from NO about what todo in the nearest second, but also in the nearest hours or days.So you need gene reprogramming."

By combining the NO and calcium ion signals in a single,simultaneous, very strong hit, "you get a profound effect ongene expression." To test this concept, he and his co-workerexposed neuronal cells in vitro to NO combined with varioustranscription inducers and monitored changes in the messengerRNAs of several immediate-early genes, of which two, c-fos andc-jun., are reported in Nature.

"These genes are the first to respond to an incoming signal;they don't need any protein synthesis," he said. "And they arethe tools that cells use to turn on other genes."

Result: When they applied NO (generated by sodiumnitroprusside) to cells along with treatments known to activateimmediate-early genes, c-fos expression was greatly enhanced,up to 50-fold; c-jun somewhat less. But the NO worked only onagents that act through calcium ions.

"The combined action of NO and calcium," the Nature paperconcludes, "leads to production of a highly active transcriptionfactor capable of reprogramming the pattern of geneexpression in neurons."

Enikolopov likes to point out that nitric oxide has been usedtherapeutically for at least a century. "People have been takingnitroglycerine for 100 years as a vasodilator for heart attacks.It turns out that nitroglycerine acts by releasing NO, whichrelaxes the heart muscle and dilates blood vessels."

Right now, he noted, "the most important application for NO isin cardiovascular research in the brain. Because of its growth-stopping properties, NO seems capable of preventing cancer,Enikolopov also noted, and many laboratories are pursuing thislead.

Being a gas, NO works at its messenger job like a very smallhormone, effective at small distances. It can diffuse from onecell that's making it to a dozen neighboring cells that are not,but which will get the message.

Meanwhile, the growing band of NO researchers has gotanother message: Where there's one gaseous hormone, theremight be others. A second colorless, toxic candidate, carbonmonoxide -- CO -- is just surfacing, and highly controversial.

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.