The objective of this proposal is to bring together a multidisciplinary group of investigators to study novel or poorly understood Ca2+ influx pathways, how these pathways are regulated and the physiological processes they control (i.e. synaptic transmission/ secretion). By combining a variety of experimental techniques including molecular biology, biochemistry, electrophysiology and [Ca2+]i measurements, we hope to aid our progress. We expect that bringing together a group of investigators with similar interests and goals but who use a variety of techniques in different preparations will aid each of the individual projects and provide a synergy not available when working alone. In project 1 - Dr. Miller will study novel Ca channels (type alpha1E) cloned in his lab (as well as others). Message for this channel is found in abundance throughout the nervous system, but functional channels have only been found in a couple of locations (i.e. cerebellum) and even there, they are rare. More in-depth studies of this Ca channel including localization and functional expression are planned. It is possible that these channels have not been identified using standard electrophysiological procedures because they are preferentially localized to synapses. In project 2 - Dr. Green will study neuronal ACh receptors in PC12 cells. Detailed studies of the pharmacological and physiological properties of these receptors are planned, with emphasis on their Ca2+ permeability. In addition, regulation and the subunit assembly of these receptors will be studied. Experiments to determine the subunit composition will continue. The goal is to gain a greater understanding of how neuronal ACh receptor diversity is achieved and the role played by these receptors in the nervous system. In project 3 - Dr. Fox will study the relationship between Ca2+ entry and secretion. Studies of membrane retrieval following stimulation are planned. The contribution made by activation of ACh receptors to secretion will be investigated. A thorough understanding of stimulus- secretion coupling and membrane recycling are essential for a complete understanding of the release process.
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