James J. Chambers

Assistant Professor of Chemistry, University of Massachusetts

Email: chambers@chem.umass.edu
J. Chambers Chemistry Web Site

Ph.D.: Purdue University
Postdoctoral Training: University of California, San Francisco and
University of California, Berkeley

Biological/Organic Chemistry
Studies of Native Proteins Using Covalent Tagging, Observation, and Perturbation

Applying novel chemical biology tools and emerging biophysical techniques to solve fundemental questions in neuroscience is the focus of my research. This includes receptor trafficking and ligand-gating, remote control of neuronal activity with chemicals and light, and computer modeling of ligand recognition by biological receptors.

Real-Time Protein Tracking: One of the main problems confronting neuroscience is a lack of understanding of the daily lives of membrane receptors. To study protein localization and dynamics, it is common to label a protein with a fluorescent tag or other contrast agent and track their motion with optical microscopy. The main strategies used for labeling are overexpression of a fusion protein and antibody-based labeling. These two methods, however, may lead to confounds based on disruption of native subunit composition or alteration of the activity of the target, respectively. Our receptor tagging method utilizes low molecular weight nanoprobes that can be remotely deployed to target specific receptors. The initial target for this project will be the subtype of the glutamate receptor called the AMPA receptor.

Using Light and Chemistry to Affect Cellular Function: Various strategies have been devised for imparting light-sensitivity onto normally light-insensitive cells to remotely control their excitability. Coupling specifically substituted photochromic molecules with endogenous proteins has been successfully used to affect the activity of living cells. Light can be used to reversibly isomerize the attached photochromic molecule causing activation or inactivation of single cells or at specific locations on a cell, such as dendritic branches or even individual spines. In addition to using this current method, we will expand the toolbox for cell control using light. Novel chemical tools that allow control of neuronal function using only chemicals and light will be a research area of tremendous wealth in the next decade.

Exploration of Small Molecule Binding Sites: The family of G-Protein-coupled receptors represents a large target for disease treatment as well as for a basic understanding of neuroscience. By using computational chemistry methods we plan to investigate further both the ligand binding sites and, more interestingly, activation mechanisms of members of the amine-binding GPCR family. We also have an interest in using this model in conjunction with library virtual screening to de-orphan orphan receptors.

Representative publications:

Chambers, J.J., Banghart, M.A., Trauner, D., Kramer, R.H. Light-induced depolarization of neurons using a modified Shaker K+ channel and a molecular photoswitch. J. Neurophysiol. 2006, 96, 2792-2796.

McLean, T.H., Chambers, J.J., Parrish, J.C., Braden, M.R., Marona-Lewicka, D., Kurrasch-Orbaugh, D.M., Nichols, D.E. C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2A Receptor. J. Med. Chem. 2006, 49, 4269-4274.

Kramer, R.H., Chambers, J.J., Trauner, D. Photochemical tools for remote-control of ion channels in excitable cells. Nature Chem. Bio. 2005, 1, 360-365.

Chambers, J.J., Gouda, H., Young, D.M., Kuntz, I.D., England, P.M. Photochemically Knocking Out Glutamate Receptors in Vivo. J. Am. Chem. Soc. 2004, 126(43), 13886-13887.

Chambers, J.J., Parrish, J.C., Jensen, N.H., Kurrasch-Orbaugh, D.M., Marona-Lewicka, D., Nichols, D.E. Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands. J. Med. Chem. 2003, 46 (16), 3526-3535.

Chambers, J.J., Nichols, D.E. A Homology-Based Model of the Human 5-HT2A Receptor Derived From an In Silico Activated G-Protein Coupled Receptor. J. Comput. Aided Mol. Des. 2002, 16 (7), 511-520.

Chambers, J.J., Kurrasch-Orbaugh, D.M., Parker, M.A., Nichols, D.E. Translocation of the 5-Alkoxy Substituent of 2,5-Dialkoxyarylalkylamines to the 6-position: Effects on 5-HT2A/2C Receptor Affinity. Bioorg. Med. Chem. Lett. 2002, 12, 1997-1999.

Chambers, J.J., Kurrasch-Orbaugh, D.M., Parker, M.A., Nichols, D.E. Enantiospecific Synthesis and Pharmacological Evaluation of a Series of Super-Potent, Conformationally Restricted 5-HT2A/2C Receptor Agonists. J. Med. Chem. 2001, 44, 1003-1010.