Molecular Basis of Transduction in Auditory Sensory Orga

Deafness &Other Communication Disorders

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Abstract

Stereocilia, are specialized actin protrusions on the surface of the sensory cells of the inner ear where the key step in the process of mechanical to electrical transduction takes place. In each cell, stereocilia are organized in bundles of precisely adjusted graded lengths forming characteristic staircase patterns. The pattern of organization and dimensions of the stereocilia are matched to specific stimulus frequency selectivity. Stereocilia are extraordinarily mechanically sensitive and can be easily disrupted by over-stimulation. An important question that follows is: How they can maintain their ordered structure, be so sensitive, and function continuously for a lifetime? The answer may be in the existence of a rapid constitutive turnover and recycling of the stereocilia molecular components. We have previously shown that the cytoskeletal core of sensory stereocilia undergoes continuous rapid renewal. However, the renewal of stereocilia membrane components remains poorly understood. We studied the spatial distribution, mobility, and trafficking of plasma membrane Ca2+-ATPase isoform 2 (PMCA2) as a model system to evaluate the extent and the mechanisms for renewal of stereocilia membrane proteins. PMCA2 is localized along the entire stereocilia membrane where it is highly abundant and uniformly distributed. We measured the rate of internalization of constitutively expressed PMCA2, we analyzed the recycling and mobility of GFP tagged PMCA2, and characterized the membrane traffic machinery present at the apical region of the hair cells. Our results show the presence of a large mobile fraction of PMCA2 with a very high lateral mobility. This mobile pool of PMCA2 mediates the uniform distribution of PMCA2 between neighboring stereocilia, as well as the exchanges between the stereocilia and the rapid internalization and delivery that takes place at the periphery of the apical cell surface. Based on our results we argue that PMCA2 and likely other stereocilia membrane proteins can turnover at fast rates, matching the previously described rapid turnover of the actin core components further demonstrating that these organelles undergo rapid renewal and continuous dynamic regulation.