Nov. 12, 1999 " this...could put researchers on the royal road to stroke treatment."
Johns Hopkins scientists have identified a new and unusual nerve transmitter in the brain, one that overturns certain long-cherished laws about how nerve cells behave.
Reporting in the current Proceedings of the National Academy of Sciences, the team led by neuroscientist Solomon H. Snyder, M.D., has also pinpointed the neurotransmitter's source -- itself a biologically unusual enzyme -- whose novelty as a drug target "could put researchers on a royal road to stroke treatment."
The neurotransmitter is an amino acid called D-serine. It's odd, Snyder says, because it differs in structure from any known molecule in its class found in mammals and other higher animals. D-serine is what chemists call a right handed amino acid. Normally, amino acids have atoms that extend from the left side of the molecule. These L-amino acids, as they're called, are the rule in vertebrates, whose biochemistry is set up to deal with these forms.
Some primitive organisms, however, notably bacteria, have a mixture of both L-amino acids and their mirror images called D-amino acids. But to find a D-amino acid in humans, Snyder says, "is unprecedented;" it's the equivalent of finding a Pterodactyl in your local pet shop.
Moreover, unlike dopamine, serotonin or other traditional nerve transmitters, D-serine isn't secreted at nerve cell endings in the brain. Instead, it comes from adjacent cells called astrocytes, which enclose nerve cells in the brain's gray matter like a glove.
The current study adds conclusive evidence to the idea that D-serine -- released from astrocytes -- activates receptors on key nerve cells in the brain. Activating these receptors, called NMDA receptors, has long been linked with learning, memory and higher thought. NMDA receptors are also known culprits in stroke damage in the brain, and have become a focus for anti-stroke research.
A body of work at Hopkins in the last five years has pointed to D-serine's role, but the new study, in which researchers have isolated and cloned the enzyme that makes D-serine, shores it up. The enzyme, serine racemase, is as unusual as its product in that it forms D-serine from L forms already in cells. "No other mammalian enzyme behaves like it," Snyder says. The oddity of having an enzyme that converts amino acids from a left to a right-handed form makes it an ideal drug target, he adds.
It invites hope that drugs inhibiting serine racemase in a timely way could damp down production of D-serine and thus squelch activity at NMDA receptors. This would be useful, during a stoke, Snyder says, when lack of oxygen in tissues triggers reactions that greatly overstimulate the NMDA receptor. Overstimulation triggers reactions that destroy nerve cells. "Being able to turn off or turn down the receptors might prevent damage," he adds.
In this study, when the scientists added L-serine to cells artificially constructed to contain the racemase enzyme, most of the L-serine was transformed to its D-serine twin. The researchers also found D-serine and serine racemase concentrated in astrocytes adjacent to NMDA receptors, but less common or nonexistent in other neural tissues.
For years, neuroscientists assumed that NMDA receptors could only be stimulated by a single neurotransmitter, an amino acid called glutamate. They now know that two neurotransmitters are needed to stimulate the receptors. D-serine was recently proposed by the Hopkins scientists as the second, largely because microscope images of tagged D-serine show it's physically near NMDA receptors in the synapse. Also, knocking D-serine out with enzymes quickly stops NMDA receptors from being active.
Hopkins researchers aren't clear why nature would have such a bizarre and highly specific neurotransmitter as D-serine, but Snyder suggests it may be because having two neurotransmitters required to trigger the NMDA receptor may be a natural fail-safe mechanism, like having two keys to the start button for a nuclear device.
"The NMDA receptor is so delicate, so crucial to us that some safeguards are in order," says Snyder. "Get too much glutamate -- one of the most abundant chemicals in the body -- and you're in trouble. But having a highly specific process to make one of the neurotransmitters could insure that activating a receptor doesn't happen by accident. The path to D-serine is pretty selective."
Other researchers in the study are Herman Wolosker, M.D., Ph.D., and Seth Blackshaw, Ph.D. The work was supported by a U.S. Public Health Service grant and a grant of the Theodore and Vada Stanley Foundation.
Under the terms of a licensing agreement between the Johns Hopkins University and Guilford Pharmaceuticals, Inc., Dr. Snyder is entitled to a share of royalty received by the University on sales of products related to the technology described in this release. The University owns stock in Guilford, with Dr. Snyder having an interest in the University share under University policy. The University's stock is subject to certain restrictions under University policy. Dr. Snyder serves on the Board of Directors and the Scientific Advisory Board of Guilford, he is a consultant to the company, and he owns additional equity in Guilford. This arrangement is being managed by the University in accordance with its conflict of interest policies
A diagram showing how the nerve synapse and astrocytes are related can be found at this Web site: http://hopkins.med.jhu.edu/synapse.html
This article, titled "Serine racemase: A Glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission," is in the November issue of The Proceedings of the National Academy of Sciences, issue 23, volume 96, pages 13409-13414.
Related articles from Hopkins: "D-Serine as a Neuromodulator:Regional and Developmental Localizations in Rat Brain Glia Resemble NMDA Receptors," by Michael J. Schell, Solomon Snyder et al. in The Journal of Neuroscience, March 1, 1997, 17(5):1604-1615.
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