Research Interests   Neurotransmitters; Neuronal Signaling

More than half of the neurons in the brain transmit signals across synapses to other neurons by releasing a burst of glutamic acid. This neurotransmitter interacts with receptors of several different subtypes on the postsynaptic cells to trigger the flow of ions across the cell membrane or to activate intracellular signaling systems. Removal of the released glutamic acid is accomplished by cell membrane-associated uptake systems, which also exist as several different subtypes and whose exact roles in the glutamic acid economy of the cells are unknown. Research in the laboratory is directed to two goals: to seek compounds that selectively activate or inhibit glutamic acid receptors and transporters, and to use these reagents to study the mechanisms of neuronal signaling.

The laboratory uses biochemical, electrophysiological and pharmacological approaches for this work. In collaboration with Drs. Robert Roon and Rodney Johnson, we have synthesized structural analogues of glutamic acid which are being evaluated for biological activity and specificity. In addition, in collaboration with Dr. Alvin Beitz, the laboratory is using immunocytochemical methods to determine the cellular localization of neurotransmitters, receptors, and transporters in the nervous system. Our current work is focused on a novel glutamic acid transporter that is localized in a discrete subset of interneurons. The glutamic acid turnover by these neurons may have a role both in the action of certain neurotoxins related to glutamic acid and to the excessive release of glutamic acid that occurs during episodes of stroke and hypoxia.

Littman, L., Tokar, C., Venkatraman, S., Roon, R.J., Koerner, J.F., Robinson, M.B. and Johnson, R.L. (1999) Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands. J. Med. Chem. 42: 1639-1647.

Roon, R.J., Koerner, J.F. (1996) Persistent depression of synaptic responses occurs in quisqualate sensitized hippocampal slices after exposure to L-aspartate-beta-hydroxamate. Brain Res. 734(1-2):223-8. (Medline citation).

Chan, P.C., Roon, R.J., Koerner, J.F., Taylor, N.J., Honek, J.F. (1995) A 3-amino-4-hydroxy-3-cyclobutene-1,2-dione-containing glutamate analogue exhibiting high affinity to excitatory amino acid receptors. J Med Chem 1995 Oct 27;38(22):4433-8. (Medline citation).

Johansen, P.A., Chase, L.A., Sinor, A.D., Koerner, J.F., Johnson, R.L. and Robinson, M.B. (1995) Type 4a metabotropic glutamate receptor: Identification of new potent agonists and differentiation from the L-(+)-2-amino-4-phosphonobutanoic acid-sensitive receptor in the lateral perforant pathway in rats. Mol. Pharmacol. 48: 140-149.

Littman, L., Chase, L.A., Renzi, M., Garlin, A., Koerner, J.F., Johnson, R.L. and Robinson, M.B. (1995) Effects of quisqualic acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus. Neuropharmacology 34: 829-841.

Price, R.H. Jr., Schulte, M.K., Renno, W.M., Koerner, J.F. and Beitz, A.J. (1994) Immunocytochemical evidence that quisqualate is selectively internalized into a subset of hippocampal neurons. Brain Res. 663: 317-325.

Vankatraman, S., Roon, R.J., Schulte, M.K., Koerner, J.F. and Johnson, R.L. (1994) Synthesis of oxadiazolidinedione derivatives as quisqualic acid analogues and their evaluation at a quisqualate-sensitized site in the rat hippocampal. J. Med. Chem. 37: 3939-3946.

Schulte, M.K., Roon, R.J. and Koerner, J.F. (1993) Quisqualic acid induced sensitization and the active uptake of L-quisqualic acid by hippocampal slices. Brain Res. 605: 85-92.