Our laboratory is interested in understanding the structure-function relationship and the mechanism of regulation of glutamate ion channel receptors. These receptors mediate rapid synaptic neurotransmission and are indispensable in the brain function, such as memory and learning. Abnormal receptor activity, however, has been implicated in various neurological diseases and disorders. To explore new, effective ways to control the receptor activity, we are also interested in developing novel reagents that are both chemical and RNA-based molecules as potential drugs and diagnostic sensors. An interdisciplinary approach is used in our research, which includes chemistry, biochemical and biophysical chemistry, molecular biology, and electrophysiology. The following are some representative areas of current projects.
- Kinetic Mechanism of Channel Opening and Structure-Function Relationship.
We are characterizing the kinetic mechanism of receptor channel opening as a way to understand the kinetic properties of different glutamate receptor subunits and isoforms. We are also interested in characterizing the effect of structural variations (either by nature, such as RNA splicing and editing, or by genetic engineering) on the receptor channel opening. For all of these studies that occur in the μs time domain, we use, among others, a laser-pulse photolysis technique with caged glutamate (a photolabile precursor of glutamate).
- Chemical Inhibitors and Mechanism of Inhibition.
Glutamate receptor inhibitors are potential drugs for a number of neurodegenerative diseases, because excessive receptor activation is known to induce calcium-mediated neurotoxicity. To develop better inhibitors as drug candidates, we are investigating how synthetic inhibitors, such as 2,3-benzodiazepine derivatives, block the receptor channel opening in the μs-to-ms time region. We are also using these compounds as mechanistic and structural probes to investigate the receptor sites of interaction.
- Developing RNA Aptamers, and RNA Structure and Function.
We are also using an evolutionary approach to select nanomolar affinity, receptor subunit/conformation-specific RNA inhibitors or aptamers from both mutagenized and random sequence libraries. These aptamers are new templates for drug design targeting glutamate receptors, and for building biosensors that may be useful in disease diagnosis. We are also studying the structural and functional repertoire of those selected RNA molecules as to how they fold to function and how they interact with the receptors using biochemical and structural methods.