Structure and function of neurotransmitter receptors
Communication between nerve cells serves as the basis of all brain activity, and one of the fundamental steps involved in signal transmission between the nerve cells, is the conversion of a "chemical" signal liberated at the end of one nerve cell, into an "electrical" signal at the second nerve cell. This step is mediated by a class of membrane bound proteins known as neurotransmitter receptors. Glutamate receptors belong to this family of proteins, and are the main excitatory receptors in the central nervous system.
Our laboratory is interested in gaining an understanding of agonist mediated activation and desensitization of this receptor by determining the structural changes in the protein induced by agonist binding. This is achieved by using various cutting edge spectroscopic methods that allow the characterization of the dynamic state structure of the proteins at a significantly higher resolution than X-ray structures. The structural changes thus determined are correlated to the functional consequences as measured by electrophysiological measurements. These investigations provide a detailed understanding of the agonist controlled function of the glutamate receptors and hence aid in the rational design of drugs targeting this group of important proteins that are involved in diverse neuropathologies, such as epilepsy and ischemia.
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| Mankiewicz KA, Rambhadran A, Wathen L, Jayaraman V. (2008) Chemical interplay in the mechanism of partial agonist activation in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Biochemistry. 47:398-404.
Du M, Ulrich H, Zhao X, Aronowski J, Jayaraman V. (2007) Water soluble RNA based antagonist of AMPA receptors. Neuropharmacology. 53:242-51.
Mankiewicz KA, Rambhadran A, Du M, Ramanoudjame G, Jayaraman V. (2007) Role of the chemical interactions of the agonist in controlling
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation. Biochemistry. 46:1343-9.
Ramanoudjame, G., Du, M., Mankiewicz, K. A., Jayaraman, V* (2006) 'Allosteric mechanism in AMPA receptors: A FRET-based investigation of conformational changes.' Proc. Natl. Acad. Sci. (Track II) 103, 10473-8.
Cheng, Q., Du, M., Ramanoudjame, G., Jayaraman, V* (2005) 'Evolution of glutamate interactions during the binding process in a Glutamate receptor. Nature Chem Biol 1, 329-332.
Du, M., Reid, S.A., Jayaraman, V.* (2005) 'Conformational changes in the ligand binding domain of a functional ionotropic glutamate receptor.' J. Biol. Chem. 280, 8633-8636.
Cheng, Q., & Jayaraman, V.* (2004) 'Chemistry and conformation of the ligand binding domain of GluR2 subtype of glutamate receptors.' J. Biol. Chem. 279, 26346-26350.
Deming, D., Cheng, Q., & Jayaraman, V.* (2003) 'Is the isolated ligand binding domain a good model of the domain in the native receptor?' J. Biol. Chem. 278, 17589-17592.
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Department of Biochemistry and Molecular Biology