Nicotinic acetylcholine receptors (nAChRs) regulate critical physiological processes in the nervous andimmune systems. These receptors represent potential therapeutic targets for new medicines to treatdisorders of motor control (e.g., Parkinson's Disease), cognition (e.g., Alzheimer's Disease andschizophrenia), and sensory perception (e.g., chronic pain). Multiple subtypes of nAChRs exist, and differentsubtypes of these receptors underlie the pathophsyiology of various disease states. However, the ability topharmacologically distinguish among these subtypes has been a problem. Conotoxins are unique peptidesthat not only are being used to overcome this problem but also serve as powerful probes for molecularcharacterization of nAChRs. We will utilize a newly discovered conotoxin RgIA, which specifically targets thealpha9alpha10 subtype of nAChR, to probe the molecular structure of the receptor. This subtype has ahighly restricted tissue distribution and was recently shown to participate in a molecular pathway ofneuropathic pain (i.e., pain induced by nerve injury). We will identify the features of RgIA that areresponsible for its selectivity and high affinity for alpha9alpha10 nAChRs. We will use this information tocreate a battery of ligands, including fluorescent ones, to study alpha9alpha10 nAChRs in their native tissueenvironment.We have also exploited conotoxins to uncover and delineate previously unrecognized binding sites on thenAChR. In this regard, Project I will continue to work closely with discovery aspects of the Program to furthercharacterize conotoxins that act at novel sites of nAChRs. Such investigation will enable further mechanisticunderstanding of the nAChR in particular and is expected to translate to improved understanding of ligandgatedion channels in general.Public Health Statement: Information from this project will help characterize a class of nervous systemrecognition molecules that are important in health problems ranging from Parkinson's disease to chronicpain. Detailed understanding of these molecules will faciltate the development of new medications to treatthese illnesses.
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