May 13, 2005 La Jolla, Calif. -- A Burnham Institute study has found that one of the cell's largest families of signaling molecules, called ephrins, which are known to regulate the development of nerve cells, also controls nerve cells' ability to engulf critical chemicals and proteins for learning and memory. These findings, the first to link these molecular semaphores to this important nerve cell function, appear in the May issue of Nature Cell Biology, published in advance at the journal's website on April 10th.
While the study's results are not immediately applicable to treating disease, they pave the way for future experiments on the roles played by ephrins in memory, learning, and other nerve cell functions, and potentially even in certain cancers.
By inserting chicken ephrin genes into rat cells, Fumitoshi Irie, Ph.D., Professor Yu Yamaguchi, M.D., Ph.D., and their colleagues found that when the ephrin subtype EphrinB activated its EphB receptor, a cascading chemical pathway was triggered that ultimately stimulated an enzyme called synaptojanin-1. This enzyme is essential for a process known as cellular endocytosis, whereby certain chemicals, viruses or other agents are surrounded with a snippet of the cell's membrane. Endocytosis important as it is the process by which cells take up materials such as neurotransmitters, fat molecules, and foreign bodies like viruses and toxins, from the external environment thus enabling the cell to store, transport or eliminate these materials.
Synaptojanin-1 enables endocytosis when it disassembles a molecular coating on storage vesicles, which allows the cell to continue making new vesicles as needed. "This was a new pathway for ephrin," said Yamaguchi. "Ephrin has been intensively studied for many years, with most attention being paid to its maintenance of the cell's skeletal structure during development."
Once the biochemical pathway was determined, the researchers then looked at whether ephrin truly increased endocytosis in cells that were not altered genetically. Using rat brain cells, they found that increased signaling did indeed create more vesicles in normal cells. Most important, these new vesicles were important parts of nerve cell synapses, the sophisticated communication relay used in the nervous system.
"We looked at the glutamate receptors at the cell synapse, and depending on other activity, ephrin appeared to decrease the number of glutamate receptors," said Yamaguchi. The regulation of glutamate receptors is crucial to maintaining memory and learning. The strength of a signal through a nerve cell synapse can be enhanced (by increasing the number of receptors) or diminished (by a receptor decrease). "The balance has to be optimal, since too much memory activation can also be a problem," said Yamaguchi.
Yamaguchi's team, which worked on this project for more than two years, had suspected that ephrins played some important part in nerve cell synapse function. Previous studies had shown that animals injected with addictive drugs had activated EphB receptors, and that there is a connection between synaptojanin-1 and bipolar disorders and schizophrenia. Until now, nobody had made the connection between EphB and the endocytosis involved in neurotransmitter regulation.
"There's also an increased interest in endocytosis in cancer, in which the process may help diminish anti-proliferation signals and, as a result, trigger tumor progression," said Yamaguchi. "But this is a novel finding in biology, and we can only just begin to speculate on the broader implications of Ephrin and EphB's activity."
Yamaguchi is a professor of developmental neurobiology at the Burnham Institute, where his research zeros in on the structure and activity of nerve cell synapses. Irie, the lead author of the paper, is a staff scientist in Yamaguchi's laboratory. Their colleagues included Misako Okuno in Yamaguchi's laboratory and Elena Pasquale, who also is a professor of developmental neurobiology at Burnham. Pasquale is an internationally known expert in ephrins and their receptors, and Yamaguchi and Pasquale have been collaborating for more than 5 years to elucidate the function of ephrins and their receptors in nerve cells.
The research was supported by a grant from the National Institutes of Health.
The Burnham Institute, founded in 1976, is an independent not-for-profit biomedical research institution dedicated to advancing the frontiers of scientific knowledge and providing the foundation for tomorrow's medical therapies. The Institute is home to three major centers: the original Cancer Center, the Del E. Webb Neuroscience and Aging Center established in 1999, and the Infectious and Inflammatory Disease Center dedicated in 2004. Since 1981, the Institute's Cancer Center has earned the prestigious designation as a Non-comprehensive Cancer Center by the National Cancer Institute. Discoveries by Burnham scientists have contributed to the development of new drugs for Alzheimer's disease, heart disease and several forms of cancer. Today the Burnham Institute employs over 700, including more than 550 scientists. The majority of the Institute's funding derives from federal sources, but private philanthropic support is essential to continuing bold and innovative research. For additional information about the Institute and ways to support the research efforts of the Institute, visit www.burnham.org.
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