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Séminaire - William N. GreenLinking Glutamate receptor distribution in PSDs to scaffold protein conformation and orientation

Abstract :

Research Statement

 My research is focused on ionotropic neurotransmitter receptors, the receptors responsible for the rapid postsynaptic response in nerve and muscle. These receptors are large oligomeric membrane proteins with subunits surrounding an ion channel that opens when neurotransmitters bind to the receptor. There are two different families of ionotropic neurotransmitter receptors. One family includes nicotinic acetylcholine receptors (AChRs), GABA and glycine receptors, and the other family are glutamate receptors, both NMDA- and AMPA-type glutamate receptors. The overall goal of my research is to understand how nerve and muscle build these receptors and traffic them specifically to and from synapses. These events regulate the number, density and function of the receptors at synapses, which helps define synaptic strength. The same events underlie learning and memory formation, and when they fail, can contribute to a number of diseases including Alzheimer’s disease, Huntington’s Disease, Myasthenia Gravis and Myasthenic Syndromes.

There are several projects ongoing in my lab characterizing the basic cell biology of these receptors, which include receptor assembly, trafficking and clustering. Assembly refers to the processes that transform newly synthesized subunits into functional receptors usually in the endoplasmic reticulum. Trafficking refers to the processes that transport the receptors to and from different location in cells and targets them to these locations. Clustering is the process that packs and maintains the receptors in regions of high density such as synapses. Recently, we have developed new techniques for assaying the protein post-translation modification known as palmitoylation. This work has led to several collaborations in which we are helping to characterize the palmitoylation of a number of different proteins. I also am collaborating with Dr. Paul Selvin (University of Illinois) developing fluorescent single-molecule methods to characterize neurotransmitter receptor subunit composition, stoichiometry and the diffusion/trafficking of these receptors.

Selected publications

Kang, R., J. Wan, P. Arstikaitis, K. Huang, A. F. Roth, R, Drisdel, W. N. Green, J. R. Yates 3rd, N. G. Davis, A. El-Husseini. 2008. Identification of the neuronal palmitoylome and its dynamics at the synapse. Nature 456:904-9. PMCID: PMC2610860

Waites, C. L., C. G. Specht, D. Genoux, R. C. Drisdel, S. Leal, D. Li, O. Jeyifous, W. N. Green, J. M. Montgomery, C. C. Garner. 2009. Distinct subsynaptic distributions of SAP97 isoforms regulate AMPAR dynamics and access to presynaptic glutamate. Journal of Neuroscience 29:4332-45.

Jeyifous, O, M. Schubert, C. G. Specht, C. L. Waites, E. Lin, S. Fujisawa, J. Marshall, C. Aoki, J. M. Montgomery, C. C. Garner and W. N. Green. 2009. SAP97 and CASK mediate sorting of N-Methyl-D- Aspartate Receptors through a novel secretory pathway. Nature Neuroscience 12:1011–1019.

Govind, A. P., P. A. Vezina and W. N. Green. 2009. Nicotine-induced Upregulation of Nicotinic Receptors: Underlying Mechanisms and Relevance to Nicotine Addiction. Biochemical Pharmacology 78:756-65.