Return to Emory Report home pageResearchers from Emory and the Salk Institute describe in a recent issue of Science "a sensible model" that links several factors related to the receptor for the important neurotransmitter glutamate. The scientists foresee the eventual application of these findings to epilepsy and stroke drug design.
Brain cell communication
Neurons (nerve cells) in the brain communicate with one another by a process known as synaptic transmission, and this intercommunication forms the basis of thought and perception, explained first author Stephen F. Traynelis, assistant professor of pharmacology at the School of Medicine and a John Merck Scholar, who conducted much of this research while at The Salk Institute in the laboratory of co-author Stephen F. Heinemann.
Messages are transmitted along the pathway connecting nerve cells with the aid of neurotransmitters -- chemical messengers that migrate across the space (synapse) between cells and bind to protein receptors embedded in the outer membrane of immediately adjacent cells. The receptors create electrical signals that move the "message" along the neural pathway.
Of these so-called neurotransmitter receptors, proteins that bind to the neurotransmitter glutamate are of particular interest, said Traynelis. They are involved in many important processes, as well as pathologic situations associated with diseases such as epilepsy and stroke.
One class of glutamate receptors, the NMDA (N-methyl-D-aspartate) receptor, mediates a signal that can be changed by many different substances in the brain. This flexible response serves numerous roles in neurobiology, one of which might be learning and memory.
One way the NMDA receptor's response can be altered is when the receptor binds with the simplest acid, the hydrogen ion, or proton. In fact, NMDA receptors are so sensitive that even the trace amount of protons present in biological fluids under normal conditions renders half of the receptors inactive.
Blocking the effect of protons -- and thus strengthening the signal between nerve cells -- may be desirable under normal conditions. But when the message the NMDA receptor transmits is a dangerous one, as during epileptic seizures -- interfering with the natural effect of protons is undesirable because protons can quiet that signal.
New findings
"In this report, we describe experiments performed using cloned NMDA receptors that suggest two other means of NMDA receptor regulation," said Traynelis. "Both simply relieve the constant inhibition by protons that exists under normal conditions. Both increase the receptor's response, one using an internal means, the other an external means."
The researchers found that proton sensitivity could be reduced internally by the production of a slightly altered receptor form that contains a small, extra stretch of protein called "exon 5." Exon 5 "shields" protons from the receptor, blocking their inhibitory actions and thus boosting the signal.
Proton sensitivity also can be reduced externally when the receptor interacts with compounds such as polyamines, which are small, positively charged molecules that exist within all cells. The researchers discovered that polyamines mimic exon 5 in their ability to shield protons from the receptor.
"The only functional difference between the two is that the small stretch of protein is tethered to the protein surface, whereas polyamines are free to move about the extracellular space between neurons," Tray-nelis said.
Significance of new findings
Many researchers have tried to design drugs that modify the NMDA receptor's function and that might be useful in treating epilepsy and stroke. However, most compounds alter NMDA receptor function too dramatically, causing side effects so profound the drugs are unusable.
"This model proposes a gentler way to down-regulate, or quiet, the signal,"
Traynelis said.
"By describing for the first time the mechanism of action of polyamines, we have in essence identified a compound that acts at the proton inhibitory site. And we've learned that polyamines mimic the naturally occurring receptor regulation of exon 5."
The researchers also described the importance of these findings in relation to acidic conditions present during seizure or stroke.
"By identifying a substance (polyamine) that acts like the exon 5 portion of the receptor, we have opened the door to the possibility that new drugs can be designed to ultimately block the effect of this exon. If non-toxic versions of such drugs can be developed, they might decrease brain damage associated with stroke by restoring the natural down-regulation of NMDA receptors. These drugs might also act as anticonvulsants."
"These discoveries certainly do not represent a cure for either of these tragic conditions," Traynelis said. "In addition, they are built upon volumes of basic research by other investigators. However, they offer hope that novel strategies can be developed to design promising new drugs for combating these diseases.
"While there is no guarantee that drugs which have the beneficial properties described above can even be found, at least we have taken another step forward in this direction."
-- Lorri Preston
Return to Emory Report home page