Educational Background:

PhD, University of California, Berkeley, 1953 BS, University of California, Berkeley, 1949

Awards:

• National Academy of Sciences • American Association for the Advancement of Science Fellow • John Simon Guggenheim Memorial Foundation Fellow • Fulbright Senior Research Scholar • National Institutes of Health Special Fellow • Alexander von Humboldt Senior Scientist Award • Cornell Merrill Presidential Scholar Outstanding Educator

Research Description:

An interdisciplinary approach involving physical and organic chemistry, instrument development, molecular biology, electrophysiology, cell biology, and computer simulation is used in investigations of the structure and function of membrane-bound proteins (neurotransmitter receptors) that control and integrate communication between the cells of the nervous system.

Receptor malfunction is implicated in many diseases of the nervous system, and the proteins are the targets of clinically important compounds, abused drugs, and pesticides. Until recently, a lack of techniques with adequate time resolution (microseconds to milliseconds) hampered investigation of the mechanism of action of neurotransmitter receptors, which must be studied in a membrane-bound form. To fill this gap, my group developed new biophysical techniques, most recently a laser-pulse photolysis method. For the new technique, we have developed, synthesized, and characterized the photochemistry and biological activity of photolabile precursors of compounds ("caged" compounds) that initiate or inhibit cell surface reactions mediated by the receptor proteins. For chemical kinetic investigations, the biologically inactive precursors are equilibrated with receptors on the surface of a single cell and photolyzed by a pulse of light from a laser; the resulting chemical reaction mediated by the receptor proteins can then be measured in the microsecond to millisecond time region (fig. 1). The immediate aim is to determine quantitative models on a physiologically relevant time scale for the reactions of both excitatory and inhibitory receptor proteins (acetylcholine, gamma-aminobutyric acid [GABA], glycine, glutamate, N-methyl-D-aspartate [NMDA], and serotonin receptors). This has already been achieved with the nicotinic acetylcholine receptor in muscle cells. The eventual goal is to integrate all the available information into a consistent mechanism of signal transmission in the mammalian central nervous system. The chemical mechanism of neurotransmitter receptor-mediated reactions is expected to set limits to the various hypotheses concerning the operation of neuronal circuits and to lead to an understanding of the effects of therapeutic agents, abused drugs, and pesticides on receptor function.

Figure 1. A clonal mammalian BC3H1 muscle cell, which contains nicotinic acetylcholine receptors, was attached to a recording electrode. The whole-cell current induced by flash photolysis of a ?caged? neurotransmitter analog equilibrated with the cell surface receptors was recorded. The current is a measure of the concentration of open transmembrane channels. Photolysis was at 328 nm with a 600-ns pulse from a frequency doubled dye laser. [From Matsubara et al. Biochemistry 31, 5507 (1992)]

Selected Publications:

Niu, L.; Grewer, C.; Hess, G. P. Chemical kinetic investigations of neurotransmitter receptors on a cell surface in the microsecond time region. Techniques in Protein Chemistry 1996, VII, 139.

Gee, K. R.; Niu, L.; Schaper, K.; Hess, G. P. Caged bioactive carboxylates, synthesis, photolysis studies, and biological characterization of a new caged N-methyl-D-aspartic acid (NMDA). J. Org. Chem. 1995, 60, 4260.

Niu, L.; Wieboldt, R.; Ramesh, D.; Carpenter, B. K.; Hess, G. P. Synthesis and characterization of a caged receptor ligand suitable for chemical kinetic investigations of the glycine receptor in the 3-microsecond time domain. Biochemistry 1996, 35, 8136.

Hess, G. P.; Grewer, C. Development and application of caged ligands for neurotransmitter receptors in transient kinetic and neuronal circuit mapping studies. Methods in Enzymology 1998, 291, 443.

Gee, K. R.; Carpenter, B. K.; Hess, G. P. Synthesis, photochemistry and biological characterization of photolabile protecting groups for carboxylic acids and neurotransmitters. Methods in Enzymology 1998, 291, 30.

Li, H.; Avery, L.; Denk, W.; Hess, G. P. Identification of chemical synapses in the pharynx of Caenorhabiditis elegans. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 5912.

Ulrich, H.; Ippolito, J. E.; Pagan, O. R.; Eterovic, V. A.; Hann, R. M.; Shi, H.; Lis, J. T.; Eldefrawi, M. E.; Hess, G. P. In vitro selection of RNA molecules that displace cocaine from the membrane-bound nicotinic receptor. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, in press.