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Affiliation: Neuroscience, Committee on Cell Physiology
Ionotropic neurotransmitter membrane receptors in ion channels
Ph.D., Cornell University
- Cellular & Molecular
- Development & Plasticity
- Neurobiology of Disease
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.
Drisdel, R. C., E. Manzana and W.N. Green. 2004. The role of palmitoylation in functional expression of nicotinic α7 receptors. Journal of Neuroscience 24:10502-10510.
Drisdel, R. C. and W.N. Green. 2004. Labeling and Quantifying Sites of Protein Palmitoylation. BioTechniques. 36:276-285.
Christianson, J. C. and W. N. Green. 2004. Regulation of Nicotinic Receptor Expression by the Ubiquitin-Proteasome System. EMBO Journal 23:4156-65. PMCID: PMC524400.
Vallejo, Y., B. Buisson, D. Bertrand and W. N. Green. 2005. Chronic Nicotine Exposure Upregulates Nicotinic Receptors by a Novel Mechanism. Journal of Neuroscience 25:5563-5572. PMCID:PMC2246082.
Yanai, A, K. Huang, R. Kang, R. R. Singaraja, P. Arstikaitis, L. Gan, P. C. Orban, A. Mullard, C. M. Cowan, L. A. Raymond, R. C. Drisdel, W. N. Green, B. Ravikumar, D. C. Rubinsztein, A. El-Husseini and M. R.Hayden. 2006. Palmitoylation of Huntingtin by HIP14 is essential for its trafficking and function. Nature Neuroscience 9:824-31. PMCID: PMC2279235.
Roth, A, F., J. Wan, A. Bailey, B. Sun, J. Kuchar, W. N. Green, B. Phinney, J. R. Yates and N. G. Davis. 2006. Global Analysis of Protein Palmitoylation in Yeast. Cell 125: 1003-1013. PMCID: PMC2246083
Wanamaker, C. P. and W. N. Green. 2007. ER chaperones stabilize nicotinic receptor subunits and regulate receptor assembly. Journal of Biological Chemistry 282:31113-23. PMCID: PMC2365492
Walsh, H., A. P, Govind, R, Mastro, J. Hoda, D. Bertrand, Y. Vallejo and W. N. Green. 2008. Upregulation of Nicotinic Receptors by Nicotine Varies with Receptor Subtype. Journal of Biological Chemistry 283:6022-32.
Liu, Y., D. Padgett, M. Takahashi, A. Sayeed, H. Li1, R. W. Teichert, B. M. Olivera, J. McArdle, W. N. Green and W. Lin. 2008. Essential roles of acetylcholine receptor gamma-subunit in neuromuscular synaptic patterning. Development 135:1957-67. PMCID: PMC2650015
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. Neural palmitoyl-proteomics reveals dynamic synaptic palmitoylation. Nature 456:904-9. PMCID: PMC2610860.
Haipeng C., S. V. Kulandaivelu, R. C. Drisdel, X. Meckler, P. Gong, J.-Y. Leem, T. Li, M. Carter, Y. Chen, P. Nguyen, T. Iwatsubo, T. Tomita, P. C. Wong, W. N. Green, M. Z. Kounnas and G. Thinakaran. 2008. S-palmitoylation of γ-secratase subunits nicastrin and APH-1. Journal of Biological Chemistry 284:1373-84. PMCID: PMC2615504
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. Synaptic SAP97 isoforms regulate AMPA receptor dynamics and access to presynaptic glutamate. Journal of Neuroscience 29:4332-45. PMCID 3230533
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- DAspartate Receptors through a previously unknown secretory pathway. Nature Neuroscience 12:10111019 PMCID: PMC2779056.
Alexander, J. K., D. Sagher, A. K. Krivnoshek, M. Criado, G. Jefford and W. N. Green. 2010. Ric-3 promotes α7 nicotinic receptor assembly and trafficking through the ER sub-compartment of dendrites. Journal of Neuroscience 30:10112-26. PMCID: PMC2945888.
Simonson, P.D. H. A. Deberg, P. Ge, J. K. Alexander, O. Jeyifous, W. N. Green and P. R. Selvin. 2010. Counting bungarotoxin binding sites of nicotinic acetylcholine receptors in mammalian cells with high signal to-noise ratios. Biophysical Journal 99: L81-L83. PMCID: PMC2980733.
Singaraja, R. R., K. Huang, J. Wan, A. Milnerwood, R. Hines, J. Lerch, S. Sanders, S. Franciosi, R. Drisdel, K. Vaid, L. Gan, C. Doty, N. Bissada, R. M. Henkelman, W. N. Green, L. A. Raymond, N. G. Davis and M. R. Hayden. 2011. Altered palmitoylation and neuropathological deficits in mice lack HIP14. Human Molecular Genetics. 20:3899-909. PMID: 3177655
Govind, A. P., H. Walsh, and W. N. Green. 2012. Nicotine-induced upregulation of native neuronal nicotinic receptors is caused by multiple mechanisms. Journal of Neuroscience 32:2227-38. PMCID: 3286518.
Baker,L.K., D. Mao, H. Chi, A. P. Govind, Y. F. Vallejo, M. Iacoviello, S. Herrera, J. J. Cortright, W. N.
Green, D. S. McGehee, P. Vezina. 2013. Intermittent nicotine exposure upregulates nAChRs in VTA dopamine neurons and sensitizes locomotor responding to the drug. European Journal of Neuroscience (in press). PMCID 3604051