investigator's application): Nerve cells interact through complex pathways that define the nervous system, but each nerve cell is a highly complex unit with individual characteristics that dictate its specific functional properties. These properties in turn define the role played by that nerve cell in carrying out a given task. Electrical excitability and impulse propagation are key to neuronal function, and these characteristics are determined at the cellular level by the exact functional properties of specific sodium and potassium channel proteins located at precise locations in the nerve cell surface membrane. Molecular-level properties of these channels and receptors are to some degree dictated by the genetic information coding for each protein type, but these properties can be profoundly changed by modifications within the nerve cell itself or by modulation due to interactions with environmental features, such as other nerve cells, chemicals in the blood or temperature. Determining the characteristics of genetically-identified channel proteins and establishing the mechanisms for biologically relevant modifications in an individual nerve cell with an identified role in a defined behavioral task is an extremely difficult problem. This research takes advantage of the unique features of giant nerve cells in the squid that carry out a simple role in escape response behavior. The genes under study encode potassium channels that are responsible for propagation of the nerve impulse, and their molecular characteristics and functional properties have been established. Work proposed here combines a number of powerful approaches to study functional modulation of these potassium channels by cellular and environmental factors. Findings from the proposed research will have broad implications for fundamental neuroscience and medicine. This work will reveal how the properties of individual nerve cells are controlled and will lead to a deeper understanding of pharmaceutical agents, including methadone and a novel compound under investigation. They will also advance our understanding of the processes that are defective in pathologies involving nerve and muscle cell excitability, including cardiac arrhythmia, and following injury to peripheral and central conduction pathways, including the spinal cord.
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