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2012 Grants - Shioi
Effect of EphB2/CTF2 Peptide on NMDAR Phosphorylation and Signaling
Junichi Shioi, Ph.D.
Mount Sinai School of Medicine
New York, New York
2012 Investigator-Initiated Research Grant
Specialized brain cells called nerve cells send rapid signals to each other by releasing packets of chemicals, known as neurotransmitters, which bind to receptors on nearby cells and induce electrical signals. One important neurotransmitter receptor in the brain is the N-methyl-d-aspartate receptor (NMDA receptor). NMDA is activated by the amino acid glutamate and is involved in learning and memory as well as signaling in the brain.
The NMDA receptor can be modified by other signaling pathways, which add phosphate chemical groups (phosphorylation) to the NMDA receptor, altering its function and characteristics. One signaling pathway thought to modify the NMDA receptor involves the enzyme gamma-secretase, which is strongly implicated in Alzheimer's disease. Gamma-secretase, also known as presenilin, is mutated in people who have one inherited form of Alzheimer's disease.
Junichi Shioi, Ph.D., and colleagues have described a cellular signaling pathway involving gamma-secretase that modifies the NMDA receptor. In this pathway, gamma-secretase cuts a protein fragment (peptide) from another receptor (the EphB2 receptor). That protein fragment, known as EphB2/CTF2 promotes phosphorylation of the NMDA receptor, changing where the NMDA receptor is located within the cell. Dr. Shioi and colleagues have proposed more extensive studies of this signaling pathway, including studies of how it is affected by genetic mutations of the gamma-secretase gene. These studies may help to explain some of the causes of neurodegeneration in people with such mutations, and they may shed light on mechanisms involved in other forms of Alzheimer's disease.