Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels found at the neuromuscular junction and throughout the CNS. Stimulation of central nicotinic receptors appears to enhance concentration and attention in normal individuals and nAChRs have been implicated in several neuropsychiatric disorders including Tourette's syndrome, Alzheimer's disease, schizophrenia, tardive dyskinesia, and Parkinson's disease. Molecular biology has shown that there are numerous subtypes of neuronal nAChRs. Unfortunately, the functional role of each of the diverse CNS receptor subtypes has not been delineated. Venom from the numerous carnivorous marine snail known as Conus contain thousands of neuroactive peptides, many of which appear to target to nAChRs. The major goal of this grant is the application of the powerful neurobiology of Conus toward the development of a bank of subtype-specific nAChR-targeted peptides. In preliminary studies, one such peptide, alpha-conotoxin ImI has been isolated, synthesized, and shown to be specific for a 7-containing neuronal nAChRs. Additional studies show that cone venoms contain other peptides which target to additional neuronal subtypes of nAChRs. The PI will use cloned nAChRs expressed in oocytes and additional methods to detect and isolate novel nAChR-targeted peptides. Purified peptides will be biochemically characterized and synthesized. The oocyte expression system as well as radiolabeling and receptor binding techniques will be used to determine the subtype specificity of the novel ligands. Such ligands would greatly help researchers determine the functional role and significance of neuronal nAChRs in neuropsychiatric health and disease.
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