Molecular and cellular mechanisms of pentameric ligand gated ion channel signaling
500 Lincoln Dr
Madison, WI 53706
Membrane Biology & Protein Trafficking; Physiology
Signaling in the brain and periphery relies on opening and closing of pentameric ligand-gated ion channels (pLGICs). Defects in pLGICs lead to a variety of human diseases. Therapeutic drugs, including muscle relaxants, sedative-hypnotics, anti-convulsants, anxiolytics and anesthetics target pLGICs. Although we know a fair amount about the structure of these proteins, how agonist binding promotes channel opening and drug binding modulates channel function remain unknown. We are using three powerful approaches: luminescence resonance energy transfer, double electron electron resonance spectroscopy and molecular dynamic simulations of fully atomistic models in conjunction with mutagenic and electrophysiological approaches to identify ligand-induced motions that underlie pLGIC function. This knowledge will improve our ability to predict the actions of drugs and ligands that act on these channels, design safer and more effective drugs, and understand how disease-causing mutations effect pLGIC function. In addition, we are working on identifying a peptide in the brain believed to be the ‘brain’s valium’. We hypothesize that the brain can enhance or inhibit GABA-A receptor mediated neuronal inhibition regionally by controlling the processing of this peptide and its cleavage products.