Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Second messenger regulation of hair cell mechanotransduction

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The broad dynamic range of the auditory system is a critically important feature, allowing it to detect stimuli at the subatomic level while at the same time not saturating for stimuli several orders of magnitude larger. In part, the dynamic range of the system is related to the ability of the hair cell mechanotransduction process to shift its activation curve by hundreds of nanometers in a calcium dependent manner known as adaptation. The second messenger cyclic AMP (cAMP) also shifts the operating range of the hair bundle, but no physiological relevance or biochemical mechanism is currently known for this process. The goal of this proposal is to explore the role of cAMP in modulating the hair bundle dynamic range at both the cellular and system level. The first aim of this research is to determine the subcellular localization of adenylate cyclase isoforms in the hair cell, since these proteins generate cAMP. The second aim explores the mechanism of cAMP action with five specific experiments: 1- determine whether inner and outer hair cells respond similarly to changes in cAMP, 2- determine the effects of cAMP on hair bundle mechanics as a means to identify the target site, 3- Photolytic release of caged cAMP will determine the kinetics of cAMP action, 4- The role of PKA in the cAMP will be determined pharmacologically and also with the use of knockout animals. 5- Whether calcium is involved in the cAMP response will be directly assayed using swept field confocal calcium imaging. The third aim will determine, the role cAMP plays in cochlear processes via the analysis of mutant mice using whole animal auditory testing of auditory brainstem responses, cochlear microphonics, and distortion products in order to understand how the system modulates the properties of the hair bundle. Together these data will provide new data regarding the biochemical pathway of cAMP regulation and also the role of cAMP in modulating hearing at the systems level.
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