Allosteric Behavior of Nicotinic Acetylcholine Receptors

Grinnell College, Grinnell IA

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Abstract

DESCRIPTION (provided by applicant): We are studying the pharmacology of human nicotinic acetylcholine receptors (nAChRs) at a molecular level. These integral membrane proteins have important physiological roles such as mediating the psychoactive effects of nicotine, and are the paradigm of ligand-gated ion channels. The compound levamisole, an agent originally used to treat parasitic worm infections, shows two modes of action at human nAChRs; it can either enhance agonist-evoked responses or inhibit them, depending on the concentration used. The current project will elucidate the mechanisms of these actions using a combination of molecular biological and electrophysiological techniques, and thermodynamic and kinetic analyses. The main focus of this work, to better understand the allosteric nature of the function of nicotinic receptors, is best categorized as basic research. However, some of the work, particularly the comparative studies of the effect of levamisole on different nAChR subtypes, is directly relevant to human health considering that levamisole is currently used in the treatments of a wide range of disorders (e.g., colorectal cancer). In addition, this work wilt contribute to emerging efforts in the development of nicotinic receptor drugs with the properties that they are not agonists themselves, but enhance endogenous cholinergic activity; levamisole displays this pharmacology on human nAChRs.