The Sensory and Motor Roles of Auditory Hair Cells
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REVIEWS The sensory and motor roles of auditory hair cells Robert Fettiplace* and Carole M. Hackney‡ Abstract | Cochlear hair cells respond with phenomenal speed and sensitivity to sound vibrations that cause submicron deflections of their hair bundle. Outer hair cells are not only detectors, but also generate force to augment auditory sensitivity and frequency selectivity. Two mechanisms of force production have been proposed: contractions of the cell body or active motion of the hair bundle. Here, we describe recently identified proteins involved in the sensory and motor functions of auditory hair cells and present evidence for each force generator. Both motor mechanisms are probably needed to provide the high sensitivity and frequency discrimination of the mammalian cochlea. Electromechanical feedback Auditory sensing in mammals occurs in a subdivision OHC contribution is known as the ‘cochlear amplifier’, The electrical change in an of the inner ear known as the cochlea, a fluid-filled a mechanism that increases both the amplitude and OHC caused by basilar tube coiled up like a snail’s shell to fit into the temporal frequency selectivity of basilar membrane vibration for membrane vibration generates bone at the base of the skull. Sound pressure fluctua- low-level sounds. The unique features of mammalian a movement of the OHC that, tions are transmitted to the cochlea in several steps: hearing — the middle ear bones, the extended basilar in turn, feeds back to or alters basilar membrane vibration. vibrations of each eardrum, conduction through three membrane and the separation of function between IHCs small middle ear bones that act in a lever-like fashion, and OHCs — have all evolved because of selective pres- Reverse transduction and production of pressure waves within the cochlea sure to extend the upper frequency limit of hearing5. In normal forward transduction, to displace the basilar membrane (FIG. 1). This com- These changes enabled the first nocturnal mammals with hair cells convert mechanical stimuli into electrical plex mechanical coup ling ensures that sound energy small heads to spatially localize the sounds made by other responses. In reverse is efficiently transferred from air to cochlear fluid animals, especially calls of their young, on the basis of transduction, the electrical over a wide frequency range1,2. Detection of the sound interaural intensity differences. signals of hair cells evoke a stimulus and its conversion to an equivalent electrical Here, we summarize recent discoveries of hair cell mechanical output. waveform, termed mechanoelectrical transduction, mechanisms underlying mechanoelectrical transduction occurs in hair cells riding on the elongated basilar and frequency tuning. We describe the newly discov- membrane. Sound-induced motion of the basilar ered proteins responsible for the precise organization membrane excites the hair cells by deflecting their of the hair bundle, many of which have been revealed hair bundles to activate mechanoelectrical transduc- by studying the genetics of hereditary deafness6 (BOX 3). tion (MET) ion channels3. Owing to gradients in the We present recent evidence about the performance and size and stiffness of the cochlear partition (the basilar molecular identity of the MET channel. Finally, we membrane and associated hair cells and supporting describe the basis of reverse transduction, which enables *Department of Physiology, University of Wisconsin cells), the place of maximal vibration varies systematic- OHCs to act as force generators and contribute to coch- Medical School, 185 Medical ally with the sound frequency like resonances in a musical lear frequency selectivity. A fuller understanding of hair Sciences Building, 1300 instrument1. As a consequence, each hair cell produces cell mechanisms may settle the long-standing question University Avenue, Madison, responses that, near the threshold of hearing, are tuned of how the mammalian cochlea achieves its remarkable Wisconsin 53706, USA. to a characteristic frequency (CF) (BOX 1). sensitivity and frequency discrimination. ‡MacKay Institute of Communication and The mammalian cochlea contains two classes of Neuroscience, School of Life hair cell, inner and outer, with distinct functions (FIG. 2). The hair bundle Sciences, Keele University, Information about the acoustic environment — speech, Actin filaments. The site of hair cell transduction is the Staffordshire ST5 5BG, UK. music or other sounds in the outside world — is relayed hair bundle, an array of modified microvilli or stereocilia Correspondence to R.F. e-mail: fettiplace@physiology. primarily by the electrical signals of inner hair cells (IHCs) arranged like a staircase in ranks of increasing height wisc.edu (BOX 2), whereas the main task of outer hair cells (OHCs) (FIG. 3). Deflections of the bundle towards its taller edge doi:10.1038/nrn1828 is to boost the stimulus by electromechanical feedback4. The bend the stereocilia at their tapered base and open the NATURE REVIEWS | NEUROSCIENCE VOLUME 7 | JANUARY 2006 | 19 © 2006 Nature Publishing Group REVIEWS Outer earMiddle Inner ear 2 days, the newly incorporated actin monomers make ear Cochlea their way down each filament and dissociate at its bottom 2 end in a process known as treadmilling (note that 0.5 0.1 turnover rates were measured in developing neonatal 0.2 5 animals and might be different in adults). Remarkably, 20 1 the speed of treadmilling is proportional to the length 10 of the stereocilium, so that in a bundle with three rows of m i different heights, actin filaments in all rows are recycled 15 s together . The steepness of the staircase is therefore pre- Cochlea Perilymph Helicotrema served by the relative rates of actin polymerization in fluid the stereocilia of each row. The same mechanism might determine the sixfold increase in maximum stereociliary 2 0.2 rw 20 height from the base to the apex of the cochlea. t A central agent in the control of treadmilling is myosin Basilar Endolymph membrane fluid XVa, a cousin of the myosin that powers skeletal muscle contractions. Antibody labelling in high-resolution microscopy has shown that myosin XVa is restricted Figure 1 | The sound conduction pathway. A section through the temporal bone to the tips of the stereocilia, the site of actin incorpora- showing the sound conduction pathway in the mammalian ear. Vibrations of the eardrum tion15,16. Furthermore, its concentration is greatest in the or tympanum (t) are relayed via three middle ear bones, the malleus (m), incus (i) and tallest stereociliary rank. Evidence that myosin XVa is stapes (s), and initiate pressure waves in the cochlear fluids, the pressure being relieved at the round window (rw). The pressure waves set in motion the basilar membrane, on necessary to determine stereociliary length comes from which the organ of Corti and hair cells ride. The cochlea is divided into compartments studies of shaker 2 mice, which have a mutation in this filled with fluids of distinct ionic composition. Perilymph is similar to extracellular fluid, non-muscle myosin. Cochlear hair cells of shaker 2 mice but endolymph, which is found in the central compartment above the tops of the hair lack myosin XVa expression and have abnormally short cells, contains a high K+ concentration and a small amount of (20 µM) Ca2+. The cochlea is stereocilia16. Other molecules might assist myosin XVa shown as straight to illustrate its internal structure, but it is normally coiled as in the inset. in regulating actin polymerization in the stereocilia: for Different sound frequencies differentially excite different regions of the cochlea, the example, whirlin, which contains multiple PDZ domains, specific locations being given in kHz from 0.1 to 20 kHz in humans. Note that the usually implicated in protein–protein interactions. Defects frequency map is logarithmic, so that each decade occupies an equivalent distance on in whirlin also cause abnormally short stereocilia in whirler the basilar membrane. The components are drawn roughly to scale for the human ear, in mice, which have hair cell pathology like that of shaker 2 which the cochlea is 35 mm in length. mice16,17. The similar phenotype suggests that myosin XVa and whirlin interact functionally. Moreover, myosin XVa is required to transport whirlin to the tips of the stereocilia16. MET channels, whereas displacements in the opposite Whirlin might behave like a scaffolding protein and, direction close these channels7. Owing to this directional through its PDZ domains, organize a group of proteins sensitivity, sinusoidal motion of the bundle about its into a functional complex at the tip of the stereocilium to resting position, as elicited by a pure tone, modulates the determine actin turnover and stereociliary length. likelihood of channel opening to generate an electrical Osmiophilic rootlet representation of the sound stimulus. Several of the Interciliary links. Stereocilia within a hair bundle are The stem of a stereocilium that molecular pathways that endow the hair bundle with its interconnected by a series of fine extracellular filaments in electron micrographs is seen (FIG. 3) to be heavily stained by precise architecture revolve around filamentous actin, . In mature mammalian hair bundles, adjacent osmium, which probably polymers of β- and γ-actin, both of which are present stereocilia are connected along their shafts by side links, indicates a dense in the stereocilia8. Stereocilia are larger versions of the whereas tip links extend from the vertex of each stereo- concentration of protein. microvilli on many epithelial cells and have a core of cilium to the side of its taller neighbour18–20. Together, actin filaments9, crosslinked with espin and fimbrin10, the links form an extracellular matrix coupling the Shaker 2 mouse A congenitally deaf mouse with spanning their length from tip to base. Most of the fila- stereocilia, so that when force is applied at the tip of the a mutation in myosin XV that ments terminate in the lower shaft of the stereocilium, bundle all stereocilia rotate together, ensuring uniform results in abnormally short where they are probably anchored to the membrane by excitation of the MET channels21.