williams

Structure, function, and regulation of glutamate receptors
Our research program is concerned with the structure, function, pharmacology, and regulation of glutamate receptors. Our long-term goals are to understand the properties of various types of glutamate receptors, their roles in the nervous system, and the mechanisms of action of drugs acting at these receptors.

The research program in my laboratory is concerned with the structure, function, expression, and regulation of glutamate receptors, with an emphasis on the N-methyl-D-aspartate (NMDA) receptor, which has the unique property of being activated not only by glutamate but by glycine at a separate glycine binding site. Glutamate receptors play a major role in excitatory signaling in the brain and are involved in the induction of various forms of synaptic plasticity. Because these receptors can also trigger neuronal cell death, they are targets for neuroprotective drugs. Some of our work is centered around understanding the molecular basis of the complex modulatory effects of polyamines, protons, and of the novel antagonist ifenprodil. A second major focus is the site and mechanism of action of open-channel blockers. Several model systems are used for these studies, which blend the concepts and questions of traditional receptor pharmacology with modern cellular and molecular techniques. Currently, our major focus involves studies of recombinant glutamate receptors expressed in oocytes. One approach involves site-directed mutagenesis and the construction of chimeric receptor subunits to define regions and individual amino acids in the receptor protein that are important for binding and/or function of particular ligands. A second, complementary approach involves the use of novel polyamine derivatives to probe glutamate receptor channels. A related project is concerned with the channel pore properties of "orphan" delta receptors.

Figure 1. Mg²⁺ block of NMDA channels.

Figure 2. Complex pharmacology of NMDA receptors.

Selected Publications

Williams, K. (1994). Mechanisms influencing stimulatory effects of spermine at recombinant N-methyl-D-aspartate receptors. Mol. Pharmacol. 46, 161-168.

Williams, K., Chao, J., Kashiwagi, K., Masuko, T., and Igarashi, K. (1996). Activation of N-methyl-D-aspartate receptors by glycine: role of an aspartate residue in the M3-M4 loop of the NR1 subunit. Mol. Pharmacol. 50, 701-708.

Chao, J., Seiler, N., Renault, J., Kashiwagi, K., Masuko, T., Igarashi, K., and Williams, K. (1997). N¹-Dansyl-spermine and N¹-(n-octanesulfonyl)-spermine, novel glutamate receptor antagonists: block and permeation of N-methyl-D-aspartate receptors. Mol. Pharmacol. 51, 861-871.

Kashiwagi, K., Pahk, A.J., Masuko, T., Igarashi, K., and Williams, K. (1997). Block and modulation of N-methyl-D-aspartate receptors by polyamines and protons: role of amino acid residues in the transmembrane and pore-forming regions of NR1 and NR2 subunits. Mol. Pharmacol. 52, 701-713.

Williams, K., Pahk, A.J., Kashiwagi, K., Masuko, T., Nguyen, N.D., and Igarashi, K. (1998). The selectivity filter of the N-methyl-D-aspartate receptor: a tryptophan residue controls block and permeation of Mg²⁺. Mol. Pharmacol. 53, 933-941.

Personnel

Takashi Masuko, Ph.D., Postdoctoral Researcher

Thomas N. Sabado, B.S., Research Technician

Service Functions

Editorial board, Molecular Pharmacology.