Nicotinic acetyicholine receptors (nAChRs) modulate the release of a number of key neurotransmitters in the central nervous system (CNS). Pharmacological manipulation of the function of these receptors may be beneficial in the treatment of a variety of disorders that impact mental health including schizophrenia, Tourette's syndrome, attention deficit hyperactivity disorder, mood disorders, Alzheimer's disease and chronic pain. Venom from carnivorous marine snails of the genus Conus are an extraordinarily rich source of compounds (cx-conotoxins) that potently and selectively target specific nAChR subtypes.
The aim of this proposal is to identify and characterize compounds from these venoms that discriminate among distinct ACh-binding subunit interfaces of neuronal nAChRs.
This aim will be accomplished by using receptor-based assays to track the purification of active venom compounds. Genes encoding a-conotoxins also will be cloned to isolate new toxins. Peptides identified by either approach will be biochemically characterized and synthesized. These peptides will then be fully characterized with respect to receptor subtype specificity and used to examine the subunit composition of presynaptic nAChRs that mediate the release of neurotransmitters. A major thrust of current research is to identify the subunits in the different functional channel subtypes of nAChRs and to understand their roles in health and disease. The availability of selective probes for the nAChR subtypes will greatly facilitate these efforts and provide a platform for development of medications capable of modulating specific nAChR-mediated functions in the nervous system.
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