Dr. S. John Mihic studies molecular sites of action of drugs of abuse on ligand-gated ion channels.

Research in the laboratory is focused on developing a better understanding of how ligand-gated ion channels function and how allosteric modulators act on these receptors. Specifically, we use molecular, biochemical and electrophysiological techniques to elucidate the processes underlying receptor activation and allosteric modulation. Most of our current research is conducted on the glycine receptor, a member of the nicotinic acetylcholine receptor superfamily, that also includes the GABAA and serotonin-3 receptors. Recently we showed that electrostatic interactions between receptor subunits keep the glycine receptor in a closed-channel state in the absence of neurotransmitter. Breakage of these bonds constitutes an initial step in receptor activation, and the particular inter-subunit interaction we studied also contributes to determining the efficacies of agonists at the glycine receptor. Many allosteric modulators affect members of this receptor superfamily including a number of sedative, hypnotic and anaesthetic agents, such as barbiturates, benzodiazepines, alcohols and volatile and steroidal anaesthetics. Using whole-cell and single-channel electrophysiology, combined with receptor subunit mutagenesis, we are conducting studies to determine the molecular mechanisms underlying ethanol and volatile anesthetics enhancement of glycine receptor function. In previous work we identified amino acid residues in the second and third transmembrane domains of subunits of GABAA and glycine receptors that control alcohol and volatile anaesthetic enhancement of receptor function. An emerging area of research interest in the lab is the use of phage display to identify novel modulators of ion channels. We recently isolated a dodecapeptide as the first potent, efficacious and highly specific allosteric modulator of glycine receptor function. Peptides specifically binding to various isoforms of GABAA receptors have also been discovered.