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date: 25 September 2017

Auditory Hair Cells and Sensory Transduction

Summary and Keywords

The organs of the vertebrate inner ear respond to a variety of mechanical stimuli: semicircular canals are sensitive to angular velocity, the saccule and utricle respond to linear acceleration (including gravity), and the cochlea is sensitive to airborne vibration, or sound. The ontogenically related lateral line organs, spaced along the sides of aquatic vertebrates, sense water movement. All these organs have a common receptor cell type, which is called the haircell, for the bundle of enlarged microvilli protruding from its apical surface. In different organs, specialized accessory structures serve to collect, filter, and then deliver these physical stimuli to the hair bundles. The proximal stimulus for all hair cells is deflection of the mechanosensitive hair bundle. Hair cells convert mechanical information contained within the temporal pattern of hair bundle deflections into electrical signals, which they transmit to the brain for interpretation.

Keywords: hair cell, sensory transduction, mechanoelectrical transduction, mechanoreceptor, sensory adaptation, auditory system, cochlea, TMC channels, usher syndrome

The Mammalian Inner Ear

The auditory and vestibular organs are formed during development by the unfolding of the otocyst, a spherical vesicle that gives rise to the inner ear. The organ of Corti arises from a ventral region of cochlear epithelium, called the prosensory domain, that runs the length of the cochlear duct. Differentiation occurs from the base of the cochlea and progresses toward the apex. Derived from surface ectoderm, hair cells face a closed compartment filled with endolymph, a unique fluid. Similar to intracellular fluids, the endolymph has a high potassium concentration and low sodium and calcium concentrations. Tight junctions that ring the apical surfaces of hair cells and supporting cells separate the endolymph from the perilymph, a fluid similar to normal extracellular solution that bathes the basolateral surfaces of hair cells. In the mammalian cochlea, ion flux from epithelial cells of the stria vascularis raises the potential of endolymph to about 80 millivolts, increasing the electrochemical gradient, which drives positively charged ions through open mechanotransduction channels. The organ of Corti is a highly specialized epithelium that contains two types of sensory hair cells, along with nerve endings and supporting cells. One row of inner hair cells (IHCs) is present on the modiolar side of the organ, and there are three to four rows of adjacent outer hair cells (OHCs). This organization is preserved along the entire length of the organ. The organ of Corti rests upon the basilar membrane, which provides graded stiffness along the cochlea and is covered by the tectorial membrane, a gelatinous acellular membrane. Both IHCs and OHCs are mechanosensory cells that detect sound pressure waves transmitted along the auditory organ. IHCs, the primary sensory cells of the inner ear, make synaptic contact with VIIIth nerve afferents and are responsible for the transmission of the signal to the central nervous system (CNS). By contrast, OHCs are signal amplifiers that generate force using active hair-bundle motility and somatic electromotility, the latter in response to depolarization that follows hair bundle displacement. These forces ensure the optimal sensitivity and sharp frequency selectivity of the mammalian cochlea.

Structure of the Hair Bundle

Auditory Hair Cells and Sensory TransductionClick to view larger

Figure 1. The structure of the auditory hair bundle. A–B: Scanning electron micrograph of hair bundles protruding from the apical surface of a P7 mouse OHC (A) and IHC (B). Mouse cochlear hair bundles are composed of 60–100 stereocilia organized in three adjacent rows. C: Transmission electron micrograph of a P2 + 1 day in culture hair bundle from a mouse OHC. Just above the apical surface, the stereocilia are interconnected by ankle links (small arrows). Shaft connectors link the lateral aspects of the stereocilia (stars). At the tip of each stereocilium are tip links (long arrows) and horizontal top connectors (arrowheads). D: High-resolution freeze-etch image of a tip link from a guinea pig cochlea hair bundle. E: Transmission electron micrograph of a P12 apical OHC. F: The tip link is formed by a PCDH15 parallel dimer interacting tip to tip with a CDH23 parallel dimer. These proteins feature 11 and 27 extracellular cadherin (EC) repeats, respectively. Inset shows possible arrangement at the junction. Scales: A, B: 1 µm. C: 200 nm. D: 100 nm. E: 200 nm.

Panel C was modified and E reprinted with permission of Journal of Comparative Neurology, by Goodyear et al. (2005). Panel D modified from Kachar et al. (2000), PNAS. Panel F reprinted with permission from Macmillan Publishers Ltd: Sotomayor et al. (2012), Nature.

The mechanosensitive hair bundle is composed of a few tens of to a few hundred modified microvilli, or stereocilia, arranged in multiple rows of increasing height (Figures 1A, B). Adjacent stereocilia adhere to each other by means of extracellular links (Figures 1C–E and 2A), so that when the bundle is deflected, the stereocilia do not separate; rather, they slide past one another. Ankle links connect the stereocilia bases (Figure 1C), shaft connectors are present along the length of adjacent stereocilia (Figure 1C), and horizontal top connectors are present just below the tips of the stereocilia (Figures 1C, E). Tip links extend from the apical tip of a stereocilium to the side of its tallest neighbor (Figures 1D, E). The stereocilia have an internal structure similar to microvilli: they are bundles of several hundred actin filaments, tightly cross-linked by the actin-bundling proteins plastin, espin, and fascin. While ranging in length from about 1 micrometer (in mammalian cochlea) to over 60 µm (in semicircular canals), stereocilia have stiff actin cores that do not normally bend, but rather pivot around their insertion point. The cores taper at their bases to a few actin filaments, which anchor the stereocilia into a cuticular plate just beneath the apical surface (Figure 2A). Many hair bundles also contain a single, eccentrically placed true cilium, the kinocilium, which, in mature cells, has the 9+2 arrangement of microtubules characteristic of motile cilia. The kinocilium may serve to organize the bundle during development. While it is lost in mature hair bundles of the mammalian cochlea, the kinocilium couples the stereocilia to accessory structures in most other organs.

Axis of Polarity

The staircase-like variation in the heights of stereocilia (Figures 1A, B) confers a morphological axis of polarity to the bundle. The positive direction is defined as being toward the tallest stereocilia (Figure 2A); the negative one is toward the shortest stereocilia. This polarity also describes the physiological axis of the bundle. A positive deflection of the stereocilia evokes an excitatory response, increasing the membrane conductance by triggering the opening of nonselective cation channels (transduction channels), allowing positively charged ions to flow into the cell and thereby depolarize it. At the bundle’s resting position, about 10% of the transduction channels are open (Figure 2B). Thus, a negative deflection decreases the membrane conductance by closing channels that are open at rest, thus hyperpolarizing the cell. This feature allows hair bundles to signal stimuli of either polarity.

The sensitivity of the hair bundle to mechanical stimuli is remarkable: a deflection of a few tenths of a micrometer in the positive direction is sufficient to activate the conductance completely, and deflections at the auditory threshold are estimated to be a few tenths of a nanometer. Side-to-side deflections of the bundle, even by several micrometers, cause no conductance change, so the cell has a vector sensitivity and senses the component of the stimulus along the bundle’s axis of polarity.

The Mechanism of Transduction

The last quarter-century has provided a good understanding of the mechanoelectrical transduction process, whereby deflections of the stereocilia cause the opening of transduction channels. The process is extremely fast: channels begin to open within about 10 µs after deflection of the bundle. This can explain a sensitivity for frequencies as high as 100 kHz in some animals, but the speed also rules out transduction mechanisms involving an enzyme cascade or second messenger molecules. Instead, it was proposed that deflections exert a force directly on transduction channels to open them, much as transmembrane voltage exerts a force directly on charged domains of voltage-gated channels. Several experiments have succeeded in measuring small movements of hair bundles that occur with channel opening. These experiments provide strong support for the idea of directly gated channels, as well as estimates of some of the mechanical properties of the transduction apparatus. The mechanical force required to open a single transduction channel is estimated to be about 2 pN, and upon opening, the channel protein undergoes a conformational change of about 4 nm.

Hair cell transduction channels are not particularly selective, passing all the alkali cations, many divalent cations including calcium, and small organic cations up to about 0.7-nm diameter. Thus, the reversal potential is close to 0 mV. Taken together with a single-channel conductance of 100–200 pS and estimates of up to 200 channels per cell (1 or 2 per stereocilium), deflections of the hair bundle can evoke transduction currents of 1 nA or more. Several independent experiments, including measurement of extracellular current and focal application of channel blockers, have localized transduction channels to the tips of stereocilia. Calcium imaging has further revealed calcium flux into mammalian auditory hair cells in shorter-row stereocilia, suggesting that transduction channels are present at the lower end of tip links. Hair cell transduction channels are opened by force applied to elastic elements, termed gating-springs, that are stretched by positive deflections of the hair bundles. Tip links seem ideally positioned to be gating-springs because they run parallel to the staircase arrangement of the hair bundle and join the top of one stereocilia to the side of its adjacent taller neighbor along the axis of polarity. The discovery that breaking tip links (for example, by treatment with low extracellular calcium) abolishes transduction provided compelling evidence that they are an essential element. High-resolution images have suggested that tip links are rigid extracellular filaments that are about 10 nm in diameter and 150–200 nm long (Figures 1D, E). They appear to consist of two or three coiled fibers with a helical period of about 25 nm and multiple globular domains of about 4 nm in diameter. Tip links are composed of two members of the cadherin superfamily, cadherin-23 (CDH23) and protocadherin-15 (PCDH15), and are formed by heterophilic and calcium-dependent interaction between homodimers, with PCDH15 at the lower end and CDH23 at the upper end (Figure 2F). The crystal structure of the N-termini of CDH23 and PCDH15 supports a novel calcium-dependent interaction with the N-terminal domain of PCDH15 in which the two amino-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer (Figure 2F). The rigid structure of the tip link suggests that the biophysically defined gating spring must be elsewhere, but still mechanically in series with transduction channels.

The Mechanotransduction Complex

Mechanosensitive channels represent a third class of ion channel in addition to those gated by voltage and ligand binding. Several mechanically gated channels have been identified in other systems, and while different candidates for the hair cells transduction channel have been proposed over the years, their definitive identity remains to be be confirmed. Four integral membrane proteins, LHFPL5 (TMHS), TMIE, TMC1, and TMC2, have been shown to be tightly involved in the mechanotransduction process. Tmc genes encode transmembrane channel–like proteins currently of unknown function. Tmc1 mutations have been linked to deafness in mice and humans. Tmc1 and its homologue Tmc2 are expressed in sensory hair cells during early stages of development, and the protein products localize to the tips of stereocilia. Genetic deletion of Tmc1 and Tmc2 causes loss of hair bundle mechanosensitivity. The conductance, selectivity, and pharmacology of the mechanotransduction channels are affected by a point mutation in TMC1. Furthermore, biochemical studies have revealed interactions between TMC1 and PCDH15, which forms the lower end of the tip links.

Taken together, these results suggest that TMC1 is an integral component of the transduction channel. Definitive proof that TMC1 is a pore-forming subunit of the channel has not yet been presented. Two other proteins linked to deafness in both humans and mice have been shown to interact with the cytoplasmic domain of PCDH15: LHFPL5, a member of the tetraspan superfamily, and TMIE, a transmembrane protein that was identified from a pull-down assay. Lhfpl5-mutant mice are deaf, and it has been proposed that LHFPL5 may facilitate the transport and assembly of the mechanotransduction channel and is functionally coupled to the tip link via interactions with PCDH15. The exact role of TMIE and LHFPL5 and how these proteins interact with TMC1 and TMC2 remain to be determined.

Molecular Basis of Hair Bundle Development

Formation of the hair bundle during development is carefully orchestrated and presumably requires precisely timed expression of a large number of genes. While some forms of deafness are associated with mutations in genes that encode surface proteins associated with stereocilia links, many others encode structural and functional proteins that are localized to the sensory hair bundle. A large number of these genes are also expressed in the photoreceptor cells and are associated with Usher syndrome. Patients diagnosed with Usher syndrome typically suffer from severe to profound hearing loss and gradual retinal pigmentosa, which leads to blindness.

Transient ankle links and side links, together with top connectors and tip links, allow the hair bundle to remain cohesive during development. Lateral links, which include ankle links, horizontal links, and top connectors, appear to be critical for normal hair bundle development and function. Ankle links, located near the base of the stereocilia, are formed by postnatal day 0 in mice and disappear by P10 in auditory hair cells. The core component of the ankle links is a member of the adhesion receptor ADGRV1 (also called VLGR1 or GRP98, the product of USH2C), a protein that spans 6,300 amino acids and is the largest G protein–coupled receptor identified to date. Other proteins, such as the transmembrane protein usherin (USH2A) and the PDZ domain-containing submembrane protein whirlin (USH2D), colocalize with ADGRV1 at the stereocilia base in developing cochlear hair cells. Horizontal links, also called shaft connectors, appear to contain the protein tyrosinase phosphatase receptor type Q (PTPRQ). Mutations in PTPRQ are associated with deafness in humans due to defects in hair cell stereocilia formation.

Stereocilin, a member of the mesothelin protein superfamily, is a component of the top connectors. While hair bundles form normally in stereocilin-null mice, they deteriorate after P9. The tip links, CDH23 and PCDH15, are also Usher proteins: USH1D and USH1F, respectively. While CDH23 is associated with the kinocilium links and transient lateral links during development, it becomes restricted to the tips of the stereocilia in mature auditory hair cells. The tip link anchor site at the upper tip link density appears to be maintained by two Usher proteins: harmonin (USH1C) and sans (USH1G) are expressed in the developing hair bundle and become focused at the upper tip-link insertion as development proceeds.

Several members of the myosin superfamily, including myosin VIIa (USH1B) and myosin XVa, also play a developmental and structural role in hair cell stereocilia. Mutations in myosin VIIa alter hair bundle morphology and, as a result, auditory and vestibular deficits occur in mice and humans. Myosin XVa is concentrated at the tip of the stereocilia, where it interacts with the epidermal growth factor receptor pathway substrate 8 (EPS8), a gene involved in actin remodeling and control of stereocilia length, as well as with whirlin (DFNB31), a scaffolding protein.

Cochlear Amplification

Mechanical amplification of sound stimuli in mammals requires the activity of OHCs that reside in three rows along the entire length of the mammalian cochlea. The process, known as cochlear amplification, functions to enhance sensitivity to faint sounds and tune or sharpen fine pitch perception. Two mechanisms have been proposed to underlie cochlear amplification: somatic motility, driven by the hair cell receptor potential, and active movements of the hair bundle, associated with channel activity and myosin motors (Figure 2).

Auditory Hair Cells and Sensory TransductionClick to view larger

Figure 2. Hair cell transduction and cochlear amplification. A: Diagram of hair bundle illustrating interciliary links that allow the bundle to remain cohesive. Tip links are formed by CDH23 at the upper end and PCDH15 at the lower end. Myosin molecules present near the upper tip link density adjust the tension applied to the transduction channel at the lower end of the tip links. Displacements toward the longest stereocilia result in gating of the transduction channel and are considered excitatory. B: Transduction currents are elicited by a 0.25-µm square step stimulus toward to tallest stereocilia. Such displacement results in fast increase in channel open probability. Over the subsequent 100 ms, the probability declines or adapts to a new steady-state level. The stimulus-response relationship (right) shifts in the direction of the applied stimulus. In the example of a positive stimulus, the curve shifts to the right (dashed line). Concomitantly to the channel opening, a decrease in bundle stiffness can be observed. The change in stiffness results from the opening of the channels. C: Two components for cochlear amplification. Current models suggest that cochear amplification may be driven by two mechanisms: active hair bundle movement and somatic motility. Active hair bundle movements may result from the interplay between adaptation and bundle relaxation. Channel opening results in bundle relaxation and a displacement of the bundle in the excitatory direction. At the same time, when calcium enters the cell via the transduction channel, fast adaptation occurs, which resets the position of the tip links and generates a negative movement of the bundle. If the bundle is moved further, transduction channels reopen. Around Popen = 0.5, the system can become unstable, oscillating back and forth between the two states. Cochlear amplification may also be driven by somatic motility in OHCs via activation of the prestin molecules densely packed along the basolateral membrane.

Somatic motility requires prestin, a voltage-sensitive membrane protein that is abundant in the lateral membranes of mammalian OHCs but absent in many non-mammalian vertebrates. The somatic motility theory for cochlear amplification posits that sound stimuli generate receptor potentials that evoke voltage-dependent conformational changes in prestin, such that the protein contracts with depolarization and expands with hyperpolarization. Because the collective motion of the densely packed molecules occurs parallel to the lateral membranes, OHCs shorten and elongate with changes in membrane potential. The force produced by somatic motility in isolated OHCs is about 100 pN/mV. Synchronous motion of OHC cell bodies with forces of this amplitude is predicted to amplify the overall motion of the basilar membrane in phase with the sound stimulus. However, because somatic motility depends on the hair cell membrane potential, the membrane time constant likely limits the ability of the receptor potential to follow the sound stimulus; thus, force production may also be limited at high frequencies to which auditory organs are known to be sensitive. Mechanisms may be present that decrease this time constant, allowing high-frequency operation. In addition, because cochlear amplification also occurs in lower vertebrates that lack OHCs and prestin, a second mechanism has been invoked.

An alternative model suggests that the forces generated in the hair bundle are sufficient to drive amplification of sound stimuli in the auditory organs of many different species. Adaptation is observed during steady deflection of the bundle in the excitatory direction, which causes an initial activation of transduction channels, followed by a decline in the response as transduction channels close (Figure 2B). The instantaneous activation curve measured after 100 ms or so is shifted to the right, relative to its position at rest (Figure 2B). Tension on transduction channels relaxes during the deflection so that additional deflection can reactivate the channels. Similarly, a negative deflection that closes channels is followed by adaptation that increases the tension and shifts the activation curve to the left. This process commonly allows hair cells to retain high sensitivity over a broad operating range and filters out slower stimuli in favor of rapid stimuli. Although the mechanism of fast adaptation is controversial, there is agreement that fast adaptation can result in active hair bundle movements. This active process arises at a point in the stimulus-response relation where there is great instability in the system, with a back-and-forth interplay between (a) transduction channel opening, (b) relaxation of the hair bundle that results from channel opening, followed by (c) rebound tension that arises from the adaptation process (Figure 2C). This phenomena, mathematically identified as a Hopf bifurcation, can contribute to bundle oscillations and may feed energy back into the organ of Corti. To tease apart the relative contributions of somatic motility and hair bundle motility will require selective inactivation in live animals. However, in mammals, both mechanisms may coexist and cochlear amplification may require both to be functional. Interestingly, while somatic motility has no intrinsic tuning, bundle motility can be tuned by the properties of adaptation.

The Receptor Potential

Because mature hair cells lack voltage-gated sodium channels, they do not generate action potentials. Rather, changes in transduction channel activity evoke graded receptor potentials of up to 40 mV. The receptor potential is modified by the activity of voltage- and ion-sensitive conductances in the basolateral membrane. In some hair cells, depolarizing receptor potentials elicit oscillations of the membrane potential, which may serve to tune the cell to a particular stimulus frequency. These oscillations result from an interplay between activation of alpha-1D calcium channels and BK calcium-dependent potassium channels. Variation in the kinetics of BK channels results from both alternative splicing and coassembly with beta subunits and gives rise to different frequencies of membrane potential oscillations, which vary systematically among hair cells of the same organ.

The ability of hair cells to signal stimuli of either polarity is preserved at the afferent synapse. At the cell’s resting potential (−40 to −50 mV), voltage-sensitive calcium channels are tonically active. This results in a steady release of neurotransmitters, which in turn results in a steady background firing in the fibers of the eighth nerve. Thus, receptor potentials of either polarity modulate calcium channel activity, and hence transmitter release. A presynaptic electron-dense body, about 0.5 μ‎m in diameter and surrounded by vesicles, is found at each release site; this synaptic body is reminiscent of the synaptic ribbon in photoreceptors and may serve a similar role in mediating continuous release. Neurotransmitter release is modulated with submillisecond precision to encode the frequency and intensity of sound and head movements. The excitatory amino acid glutamate has been shown to be released by hair cells, but it is not clear whether it is the primary transmitter or whether other transmitters are coreleased.

The efferent synapse, carrying feedback control from the CNS via the olivocochlear fibers, uses acetylcholine as the transmitter. The synapse may be excitatory in some hair cells, but in most organs, efferent stimulation causes a slow, inhibitory hyperpolarization. The inhibition is caused by slow activation of calcium-dependent potassium channels (SK). SK channels are voltage insensitive and can be activated by micromolar concentrations of calcium. The α‎9 and α‎10 nicotinic cholinergic subunits have been shown to form the receptor that mediates synaptic transmission between the efferent fiber and hair cells. The high calcium permeability of this receptor may permit sufficient calcium entry to activate SK calcium-dependent potassium channels, which in turn inhibits the cell.


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