CAA: Molecular Basis for the Cholinergic Modulation of Auditory Hair Cell Properties

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In the mammalian inner ear a subpopulation of the sensory cells receive inhibitory inputs from the brain. Neuronal feedback pathways such as this one, from the brain to the sensory organ are called efferent or descending pathways. Similar neural feedback modulates sensory perception also in the lateral lines of fish and in the inner ears of reptiles, amphibians, and birds. The fact that this efferent inhibition has been conserved across animal classes suggests the fundamental importance of this process. This auditory efferent pathway contributes to the exquisite sensitivity and frequency selectivity of our sense of hearing by modulating the excitability of the sensory cells. However, the mechanisms underlying this modulatory feedback are not understood at the molecular level. It is known that the acetylcholine receptors alpha 9 and alpha 10 and the small conductance Ca2+-activated potassium channels SK2, which are often co-localized with calcium sources are required molecular components in the mammalian auditory sensory cells. This project applies a molecular biology strategy to identify proteins involved in the selective localization, clustering, and functional associations between these ion channels. Additionally, fluorescently tagged chimeras of the SK2 and of the alpha 9/ alpha 10 receptors have been constructed to apply state-of-the-art optical techniques to the investigation of the biochemical basis of their functional interactions. The findings will advance our understanding of the biochemical principles underlying sensory perception including protein-protein interactions between the ion channels involved. While completing this project graduate students and post-doctoral fellows will be trained to utilize powerful electrophysiological and optical research techniques as well as biochemical and molecular techniques. These are essential techniques in neuroscience and other biological research frontiers for which a detailed understanding of macromolecular complexes harboring ion channels in excitable cells is fundamental.