Faculty Research Interest

Neurotransmitter-Gated Ion Channels: Structure, Function and Pharmacology
Malaria Parasite Physiology and Mechanisms of Chloroquine Resistance

Faculty Record

Neurotransmitter-gated ion channels are essential components in synaptic transmission. Our work focuses on the GABAA receptor, the major post-synaptic inhibitory neurotransmitter receptor in brain. It is the target for drugs used clinically in the treatment of anxiety and epilepsy, and for general anesthesia. GABAA receptors are members of a gene superfamily that includes receptors for glycine, acetylcholine, and serotonin. Our goals are to understand the structural bases for the functional properties of the channel and to understand the molecular interactions by which drug binding modulates structure and channel activity. We use a combination of techniques including site-directed mutagenesis, heterologous expression, covalent chemical modification and electrophysiology. These studies have identified the residues lining the channel, the location of channel blocker binding sites and identified conformational changes occurring during channel gating and modulation by drugs including valium and propofol.

Malaria is a major public health problem affecting large areas of the world, killing several million people, mostly children and pregnant woman, each year. Malaria is caused by unicellular parasites from the Plasmodium species that grow inside erythrocytes. We have been studying two aspects of the biology of Plasmodium falciparum that causes the most lethal form of malaria. One project focuses on the protein responsible for chloroquine resistance in malaria, the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT). PfCRT is an integral membrane protein with 10 putative membrane-spanning segments that is expressed in the parasite's digestive vacuole. In collaboration with Dr. David Fidock's lab (M & I) we have been expressing PfCRT in heterologous cells in order to probe its function, trafficking and interactions with chloroquine. The second project focuses on the physiology of the parasites during their 48 hour intraerythrocytic life cycle. We are characterizing the physiological changes that occur and the effects of anti-malarial drugs on the normal intracellular physiology.