Auditory sensation begins with the collection of sound energy by the external ear. Sound is carried as a mechanical vibration through the middle ear and into progressively smaller structures in the inner ear, where it finally causes an oscillating force on mechanically sensitive ion channels in hair cells. Sensory transduction — the process of converting the physical stimulus to a neural signal — begins when the force opens and closes these channels, cycle by cycle, to allow a pulsatile flow of ionic current into the receptor cells.FIG1 

Panel A

A cross-section of the human auditory apparatus (image reproduced with permission from A. Greene and N. Kiang, Eaton-Peabody Laboratory,Massachusetts Eye & Ear Infirmary). The external ear (the pinna) collects sound and funnels it into the ear canal, where it causes vibration of the eardrum (the tympanic membrane). The tympanic membrane drives a vibration of the three middle ear bones: the malleus (attached to the tympanic membrane),the incus and the stapes. The footplate of the stapes then drives the oval window, a flexible membrane separating the air-filled middle ear from the fluid within the cochlea. The ossicles perform an impedance-matching function,converting the high-amplitude, low-force vibration of air to a low-amplitude,high-force vibration in the fluid of the cochlea. The inner ear comprises organs of two sensory systems: the vestibular organs (the saccule, utricle and three semicircular canals) sense tilt and movement of the head, and subserve the sense of balance. The snail-shaped cochlea (spiraling through three turns in humans) senses the vibration of sound and subserves hearing.

Panel B

A cross-section of one turn of the cochlea. Each turn has three fluid spaces with differing ionic composition: while the perilymph in scala tympani and scala vestibuli (ST and SV) is much like normal extracellular fluid, the endolymph in scala media (SM) has a high K+, low Na+ and low Ca2+ composition like intracellular fluid and a standing voltage of about +80 mV. The basilar membrane, a flexible structure like a very long drumhead, separates scala tympani from scala media. The oval window connects to the scala vestibuli, so that the compression phase of each cycle increases pressure in the scala vestibuli and scala tympani, pushing down on the basilar membrane. The rarefaction phase pulls back up. Riding on the basilar membrane is the organ of Corti, which contains the sensory receptor cells — one inner hair cell (IHC) and three outer hair cells (OHC) in each cross-section — and adjacent supporting cells. Nearby cells secrete the tectorial membrane (MT), a filamentous extracellular structure that overlies the organ of Corti and attaches to the tops of hair cells. [Reprinted with permission from the American Association for the Advancement for Science(Core and Garcia-Anoveros, 1996).]

Panel C

Scanning electron micrograph of the organ of Corti with the tectorial membrane (TM) pulled back and a section broken away to reveal the cell bodies of hair cells (red). Both inner hair cells (IH) and outer hair cells (OH) have a tuft of cilia (the hair bundle) emanating from their apical surfaces [image reproduced with permission from Butterworths NexisLexis(Hunter-Duvar, 1984)].

Panel D

Coupling of basilar membrane vibration to hair cell stimulation. Because the tectorial membrane is anchored at a site distant from the basilar membrane insertion, sound-evoked vibration of the basilar membrane causes a shearing movement between the tectorial membrane and the organ of Corti. The tectorial membrane is attached primarily to the tips of stereocilia, so an upwards movement of the organ of Corti produces shear that deflects stereocilia to the right. There may also be more complex vibrational modes.

Panel E

SEM of hair bundles of four outer hair cells (image reproduced with permission from B. Kachar, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD). In mature hair cells of the mammalian cochlea, all of the cilia are stereocilia,and have an internal structure of ordered, crosslinked actin filaments that makes stereocilia stiff and straight. In all vertebrate hair cells, the heights of stereocilia increase uniformly from one row to the next. However the overall height, width and shape of the bundle vary among organs and species; as seen here, outer hair cells of the mammalian cochlea have a V- or W- shaped bundle.

Panel F

SEM of three hair bundles from the bullfrog saccule. These hair bundles,from a vestibular bundle, have a circular arrangement of stereocilia but again show the staircase-like increase in height. In common with most hair cells,they have a single kinocilium adjacent to the tallest stereocilia. The bundle on the left — oriented oppositely from that in the upper right —shows the more sinuous kinocilium, which has an internal structure of microtubules like those of motile cilia. It ends in a bulb in these bundles but has uniform diameter in others. (Image reproduced with permission from J. Assad and D. Corey, Harvard Medical School, Boston, MA)

Panel G

SEM of the tips of stereocilia in a saccular hair cell [image reproduced with permission from Elsevier Science(Assad et al., 1991)]. Extending between the tip of each stereocilium and its taller neighbor is a fine extracellular filament called a tip link, which runs along the axis from short to tall but not from side to side. Hair cells respond physiologically to deflections of the bundle along this axis (panel I), but not from side to side. Cutting the tip links chemically abolishes the physiological response,but responsiveness returns when tip links regenerate in 5-10 hours.

Panel H

Transmission electron micrograph of two stereocilia and the tip link between them [Image reproduced with permission from Elsevier Science(Assad et al., 1991)]. Tip links are generally ∼150 nm long and 8-11 nm thick, and are apparently a helix of two filaments. An intracellular osmiophilic density is present between the cell membrane and the nearest actin filaments at either end of the tip link. The dense core of actin filaments is also seen in these stereocilia.

Panel I

A model for mechanical transduction [Image reproduced with permission from Science (Corey and Garcia-Anoveros, 1996)]. Electrophysiological recordings show that deflection of a hair bundle opens — within microseconds —transduction channels that are located near the tips of the stereocilia. The speed of the response suggests that the mechanical stimulus is conveyed directly to the ion channel protein. Because of the staircase geometry of the bundle, such deflections would tend to stretch the tip links. A particularly attractive hypothesis for transduction is that tip links are connected at each end to transduction channels in the stereocilia membrane. These would be anchored in turn to the actin cytoskeleton, so that stretch causes tension on the channel protein, and promotes a conformational change to open the channel pore. Deflections that relax tip-link tension would allow channels to close. Cochlear hair bundles oscillate at the sound frequency (at 100 kHz or more in some animals) and the speed would allow channels to open and close with each cycle of the sound. The transduction mechanism is also very sensitive: the deflection at perceptual threshold can be less than 1 nm, and the entire sensitive range corresponds to deflection of 100-1000 nm or to a tip-link stretch of 10-100 nm. The molecular identities of neither transduction channel nor tip link are known.

Panel J

Cartoon of the transduction apparatus with a motor complex [Image reproduced with permission from Elsevier(Gillespie and Corey, 1997)]. Because small static deflections of a bundle could open or close all the transduction channels, rendering a hair cell insensitive to small vibratory stimuli, hair cells also have several mechanisms to regulate or bias the open probability of transduction channels. One such mechanism apparently involves a cluster of myosin molecules that anchor a channel to the actin core. It is thought that this motor complex, at the upper end of each tip link, is continuously trying to climb the actin of its stereocilium. At some tension the motor slips as fast as it climbs, and the stall force is just sufficient to keep channels open 10-15% of the time. A deflection that increases tension and opens channels (to the right in panel I) also causes the motor to slip down in 10-100 milliseconds, allowing channels to close again and thus acting as an adaptation mechanism. A deflection to the left that relaxes tension and closes channels allows the motor to climb up and restore resting tension. The motor protein is known: it is myosin-1c, a small myosin of the type I family,which is probably regulated by the binding of calcium-calmodulin to its neck region. The connections to other myosins and to the channel, shown here, are purely speculative.

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