Biochemistry: Function and structural changes of the protein complexes involved in synaptic plasticity.
Ph.D., , University of Tokyo
M.D., , University of Tokyo
Awards and Academic Honors
John Merck Scholarship
Hellman Faculty Fellow
HHMI Postdoctoral Fellow
Massachusetts Institute of Technology
Human Frontier Science Program Long-Term Fellow
Massachusetts General Hospital, Harvard Medical School
Molecular mechanism of synaptic plasticity.
Neurons in the brain form neural circuits by making contact with each other at the structures known as synapses. In many cases, electrical signals are converted to chemical signals at the synapses and transmitted from one neuron to another through the mechanisms of synaptic transmission. At the synapse, protein complexes formed of ion channels and soluble signaling proteins function in regulating synaptic transmission. My laboratory is interested in understanding the changes of these macromolecular machineries (i.e. changes in composition, conformation, and modification) in response to neuronal activity. Our primary focus will be on glutamate receptors and their macromolecular assembly formed of scaffold proteins. We combine techniques in molecular and cellular methods, biochemistry, and imaging to accomplish the task. Studying the mechanisms of synaptic function is likely to tell us more about the normal physiology and pathology of the nervous system at the molecular level.
(1) Understanding the structural basis of AMPA receptor function using cryo-EM
Development of a purification method to isolate intact AMPA receptors from the brain allows us to study the structural basis for the function of these important ligand gated ion channels in the synapse. Based on the 35 Angstrom density map we published in 2005 and 2006, we are currently working on to obtain higher resolution structure of the intact tetrameric AMPA receptors using cryo electron microscopy. We expect to understand the accurate subunit arrangements within the tetrameric AMPA receptors and further obtain clues to the glutamate induced conformational changes.
(2) Molecular mechanism of the functional modulation of AMPA receptors by stargazin/TARP
Modulation of AMPA receptors affects synaptic plasticity at the cellular level and influences cognition at the level of behavior. Membrane proteins in the stargazin/TARP family are auxiliary subunits of native AMPA receptors in the brain and modulate ion channel functioning by slowing down the desensitization kinetics. Using electron microscopy and electrophysiological recordings, we intend to further identify the mechanism of the modulation of AMPA receptors by stargazin/TARP.
(3) Determining the modular organization of the synaptic plasticity machinery
Through the approaches taken by molecular cloning and protein identification through mass spectrometry, neuroscientists have the overall view about the variety of the molecules (mainly proteins) that exists in the synapse. It remains less known how these proteins assemble and exert their functions during synaptic plasticity. On the assumption that modular organization of macromolecules forms the basis of synaptic structure and function, we intend to isolate and characterize novel protein complexes involved in synaptic plasticity. By accumulating the information on the variety and function of macromolecular machinery in the synapse, we intend to provide an explanation for the modular organization of the synapse.
Primary Research Area
- Epub 2005 Sep 12. Generation of lentiviral transgenic rats expressing glutamate receptor binding protein 1 (GRIP1) in brain, spinal cord, and testis. With Feliu-Mojer. M.I., Wulf. P., Lois. C., Sheng. M., and Hoogenraad. C.C. J. Neurosci. Methods. 152(1-2):1-9. Epub 2005 Sep 12. (2006)
- Three-dimensional structure of an AMPA receptor without associated stargazin/TARP proteins. With Cheng. Y., Sheng. M., and Walz. T. Biol. Chem., 387(2): 179-187. (2006)
- Structure and different conformational states of native AMPA receptor complexes. With Cheng. Y., Ramm. E., Sheng. M., and Walz. T. Nature, 433: 545-549 (2005).
- Quaternary structure, protein dynamics and synaptic function of SAP97 controlled by L27 domain interactions. With Futai. K., Lashuel. H. A., Lo. I., Okamoto. K., Walz. T., Hayashi. Y., and Sheng. M. Neuron, 44: 453-467 (2004)