Myles Akabas, M.D., Ph.D.

NEUROTRANSMITTER-GATED ION CHANNELS: STRUCTURE, FUNCTION AND PHARMACOLOGY

Neurotransmitter-gated ion channels are essential components in synaptic transmission. They are a major target for drugs used clinically including general anesthetics. Our work focuses on the GABA_A 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. GABA_A receptors are members of a gene superfamily that includes receptors for glycine, acetylcholine, and serotonin. We seek to provide a molecular understanding of the structural bases for receptor function, modulation by drugs and cellular trafficking. This would provide a basis for rational drug design and an understanding of the molecular mechanisms by which general anesthetics function. 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 PARASITE PHYSIOLOGY AND MECHANISMS OF NUCLEOSIDE AND DRUG TRANSPORT

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 mechanism of purine transport into P. falciparum. Malaria are purine auxotrophs and require an exogenous source of purines to survive. We seek to characterize the purine nucleoside transporters and identify inhibitors as potential antimalarial drugs. 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.