Acetylcholine receptors are key elements of synaptic transmission and neuronal signal transduction. The proposed studies will focus on the role of the neuronal nicotinic acetylcholine receptor during development of the nervous system of Drosophila. We will carry out a genetic analysis of this receptor in vivo by introducing mutations into two genes encoding an alpha-subunit (als) and beta-like subunit (ard). These two subunits form part of one of the subtypes of a neuronal nicotinic acetylcholine receptors in Drosophila. Results from these studies will allow us to analyze the effect of various mutations in the receptor on the development, structure and function of the nervous system. These studies have also biomedical relevance since it was found recently that mutations in the receptor in humans lead to epilepsy. In the second part of our proposal we will carry out a genetic screen to identify targets of nicotine action in the nervous system of Drosophila. The molecular mechanisms to be identified in nicotine action might be part of the signal transduction cascade through nicotinic acetylcholine receptors (nAChR); alternatively nicotine action might involve components yet to be identified. Knowledge of these pathways might contribute to our understanding of nicotine addiction in humans. Structural analysis of this neurotransmitter receptors has also significance for a rational design of insecticides.
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