Our research aims to define atomic structures of postsynaptic receptors and delineate molecular mechanisms underlying their function. We focus on nicotinic receptors at the neuromuscular junction and in brain, and on understanding how agonist binding is transduced into opening of an ion channel intrinsic to the receptor. Experimental approaches include molecular biological methods for manipulating receptor structure, expression of receptors in mammalian cells, measurements of ligand occupancy, protein biochemistry, high resolution single channel recording coupled with a battery of kinetic analyses, molecular modeling of receptor structure, molecular docking of ligands and molecular dynamic studies. We also unmask key structural and functional leverage points by delineating mechanistic underpinnings of congenital myasthenic syndromes, diseases that produce profound muscle weakness.
Because of their position in the pathway of information flow, postsynaptic receptors are logical targets for learning and memory processes, pathologic processes, and therapeutic drugs. Thus, our studies contribute to the fundamental molecular foundation essential for understanding synaptic transmission in normal and disease states, and drug action at motor synapses. Future research will follow two parallel paths. Firstly, we will extend our studies to postsynaptic receptors found in brain in normal and pathologic states. Secondly, we will continue to delineate structurally unknown regions of nicotinic receptors, employ molecular docking studies to understand drug action and implement molecular dynamics to describe molecular motions underlying nicotinic receptor function.