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.
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Nature Cell Biology