Natural gas. A complex of calcium and calmodulin stimulates HO2 to produce carbon monoxide.

Just Say CO

For years, scientists assumed that neurotransmitters, the molecules that transmit messages between neurons, were neatly stored in tiny vesicles. So it was big news when neuroscientists discovered a dozen years ago that a gas--nitric oxide (NO)--could function as a neurotransmitter, because gases cannot be stored in vesicles. Now, they have data that strongly suggest that another gas is also a member of the neurotransmitter club: carbon monoxide (CO).

CO is made by an enzyme called heme oxygenase. One form, HO1, releases CO in aging red blood cells. But the function of HO2, a second type that's found in the brain, was mysterious until the early 1990s. Then-graduate student Ajay Verma, in Solomon Snyder's lab at Johns Hopkins University, wondered if the enzyme might produce CO as a neurotransmitter. Verma and his colleagues soon determined that HO2 exists in discrete brain regions, as one would expect of a neurotransmitter, and CO appears to influence key brain enzymes and control intestinal function and ejaculation in mice.

A key piece of evidence was still missing. Researchers had no idea how CO production was regulated--a gaping hole, considering that gases cannot be stored for release and must be made on demand when a neuron is stimulated. The first clue to CO's regulation emerged in the 25 September issue of Neuron, when Johns Hopkins postdoctoral fellow Darren Boehning showed that an enzyme called CK2 can activate HO2 by sticking on a phosphate group. CK2, in turn, is activated by protein kinase C, an enzyme that is turned on whenever a neuron fires.

But there is a second, faster mechanism, Boehning reported at the Society for Neuroscience meeting in New Orleans on 11 November. In a random search for proteins, Boehning found that one called calmodulin adheres strongly to HO2. Calmodulin also binds to nitric oxide synthase, which then produces NO whenever a neuron fires and receives a big dose of calcium. Boehning immediately realized that CO might be made in similar fashion. "It was a eureka moment," he says. He went on to show that calcium and calmodulin activate HO2 in a test tube, while inhibitors of calmodulin block HO2 activity. Boehning suspects that a calcium-calmodulin complex turns on the enzyme in response to millisecond pulses of neuronal activity, while CK2 activates it for seconds to minutes.

The case for CO's role as a neurotransmitter "is greatly strengthened by the new finding," says neuroscientist David Bredt of the University of California, San Francisco. Indeed, the evidence for both mechanisms suggests that CO may be involved in a neural signaling pathway "of major importance," adds Paul Greengard of Rockefeller University in New York City. If the pathway is similar in humans, it could lead to new treatments for diseases of the gastrointestinal tract, Snyder says--or for premature ejaculation.

Related sites
Abstract of the talk
Abstract of the paper in Neuron