July 27, 1998 Researchers have long known that the wily marine snail known as conus geographus uses a toxic venom to stun its prey into submission.
Now, researchers led by a UC San Francisco scientist have determined that proteins extracted from the venom prevent serotonin, a key chemical messenger in the nervous system, from acting at a particular molecular gateway, or receptor, in African toad eggs. The receptor is also found in the human brain.
The finding, reported in the current issue of Science, could provide a model for exploring the way in which serotonin and several other neurotransmitter receptors are regulated in humans, according to one of the authors of the study,
David Julius, PhD, an associate professor of cellular and molecular pharmacology at UCSF. And as serotonin plays a key role in regulating nerve cell behavior, understanding the way in which it functions paves the way for designing new drugs to control its actions.
One existing drug that targets the receptor, known as 5-HT3, is used to treat nausea that accompanies chemotherapy. Drugs targeting the receptor could potentially be designed to treat pain and anxiety, said Julius.
Serotonin and the hundreds of other neurotransmitters zipping through the brain act as chemical messengers between nerve cells. They are released from one neuron and move at the rate of milliseconds to another, where they bind to a particular molecular gateway within the cell. There, like a key turned in a keyhole, they "unlock" the gateway, transmitting their chemical message into the cell, telling it either to fire an electrical output, or nerve signal, or hold off on firing.
The ultimate goal of the current study, said lead author Laura England, PhD, a postdoctoral candidate in Julius's lab, is to use the toxins that have been isolated to probe the site at which serotonin binds to the receptor and understand what the molecular pocket at which it binds looks like.
"If you can do that, and figure out what the molecular contacts are between a neurotransmitter and its receptor, then you have the information you need, potentially, to design drugs," she said.
While the study focused on proteins found in a species not usually likened to humans, the leap to the human nervous system is not unrealistic, as much of the human nervous system is made up of molecules that have been conserved through evolution. The marine snail toxins have long been known to act on numerous cell receptor families within the mammalian nervous system. What hadn't been known is that they act on serotonin receptors.
As there are already numerous good drugs that act on this particular serotonin receptor, 5-HT3, it is unclear whether the research will lead to the design of better drugs, said Julius. However, the receptor is a member of a large family of receptors and contains the same structural motif as the receptors for the neurotransmitters acetycholine, GABA and glycine. Therefore, he said, "it provides a model system for understanding how this big class of channels works."
While researchers do know that the toxic peptides released by marine snail venom rapidly immobilize prey by creating neuromuscular and sensory blockades and stimulating shock, they do not know for certain that this occurs in part as a result of serotonin inhibition. It is possible, however, that this a contributing factor, said Julius.
Researchers from the University of Utah, including Baldomero M. Olivera, and The Salk Institute for Biological Studies, including A. Grey Craig and Jean Rivier, also participated in the study.
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