The Function and Molecular Identify of Inward Rectifier Channels in Vestibular Hair Cells of the Mouse Inner Ear

In vestibular hair cell signaling mechanical stimuli are transduced into graded receptor potentials. Several ionic conductances in the basolateral hair cell membrane have been identified that modify these receptor potentials before vestibular ganglion neurons encode and transmit them to the vestibular nuclei in the brain stem. To fully understand inner ear hair cell signaling, it is important to define the molecular identity of these conductances. For this thesis I examined the molecular correlate of the potassium inward rectifier current (I K1 ) and determined its role in inner ear hair cell signaling. Previously, I K1 has been identified in hair cells of a variety of model systems including frog, mouse and avian species. However, its molecular composition and functional contributions remained elusive. Of the four members of the potassium inward rectifier (Kir2) channels only transient expression of Kir2.1 has been described in the mouse cochlea, but not in the vestibular system. Therefore, to fully understand how Kir2 channels contribute to sensory hair cell signaling I focused on two specific aims: First to characterize expression patterns of Kir2 family ion channel genes in mouse vestibular hair cells. And secondly, to examine the function of candidate Kir2 family ion channel genes in vestibular hair cell signaling. For the first aim I used quantitative RT-PCR showing that expression of Kir2.1 mRNA coincides with the onset of I K1 in mouse utricle early in development. In addition, I confirmed Kir2.1 protein immunolocalization to the basolateral membrane of hair cells. For the second aim I examined the physiological properties of sensory hair cells using the whole-cell, tight-seal recording technique. In addition to pharmacological blockers I used Kir2.1 knock-out mice and adenoviral dominant-negative constructs to look at the functional contribution of Kir2.1 to vestibular hair cell signaling.

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