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British Medical Bulletin 63:59-72 (2002)
© 2002 The British Council

Biophysics of the cochlea – biomechanics and ion channelopathies

Jonathan Ashmore

Department of Physiology, University College London, London, UK


   Abstract
Top
 Abstract
Introduction
 Cochlear mechanics
 Channelopathies
 Conclusions
 Key points for clinical...
 References
 
Understanding how the cochlea works as a system has become increasingly important. We need to know this before integrating new information from genetic, physiological and clinical sources. This chapter will show how the cochlea should be seen as a device for carrying out a frequency analysis built from cells that have been adapted for specialist purposes. Sensory hair cells convert mechanical displacements into the neural code. The transducer channel remains to be identified. The biomechanics of the cochlear duct depends on an energy-dependent feedback from the sensory outer hair cells. The molecular basis for outer hair cell feedback depends on a protein that has recently been identified. The auditory signal encoded by the cochlea is further modified by membrane properties of the hair cells and cochlear supporting cells. The interplay between techniques of genetics, molecular biology and cell physiology has started to reveal which ion channels and transporters in the cochlea are mutated in certain forms of deafness. The interpretation of these mutations requires the cell physiology of the cochlear partition to be better characterised in the future.


   Introduction
Top
 Abstract
 Introduction
Cochlear mechanics
 Channelopathies
 Conclusions
 Key points for clinical...
 References
 
There have been significant steps in the way in which we understand the cochlea. Over the past decade, the question of which molecules participate in hearing has been brought from speculation to the laboratory bench. Although some of the techniques for studying cellular physiology were starting to producing new insights when the last British Medical Bulletin survey of the field was made in 1987, the introduction of molecular biology techniques into hearing research has driven many developments. The barrier of limited tissue sample quantities in hearing no longer seems to be so insurmountable as 10 years ago. Modern molecular techniques aided by genomic searches now have the ability to identify the small numbers of molecules present in the inner ear.


   Cochlear mechanics
Top
 Abstract
 Introduction
 Cochlear mechanics
Channelopathies
 Conclusions
 Key points for clinical...
 References
 
It has long been appreciated that the mammalian cochlea is designed to analyse the frequency components present in complex sounds. It does this using the mechanical properties of the cochlear partition. The principles have been understood for well over 60 years when the physics was first encapsulated by simple mathematical models. In the majority of these models, the cochlea is simplified to a fluid-filled tube with a membrane, the basilar membrane, dividing it lengthwise. As explored by von Békésy in the 1940s, the stiffness gradient along the partition sets up a frequency map so that differing frequencies are associated with different resonant excitation sites. The wave motion along the basilar membrane induced by sound entering the inner ear can now be modelled with reasonable accuracy on a small computer1. The cochlea thus behaves as a mechanical spectrum analyser over the full auditory range.

The resulting design works reliably and with stability at frequencies that may extend above 10 kHz. For some mammals, the upper auditory range may extend 2–3 octaves above this frequency. Over the past 15 years, methods for measuring basilar membrane mechanics have improved considerably, mainly due to the appearance of a new generation of interferometers for measuring the nanometre scales of basilar membrane displacements2–4. Some of these instruments have been designed to measure motions of relatively low reflecting surfaces4,5. Experiments in in vivo animal models show that at the threshold of hearing (0 dB SPL) the amplitude of the basilar membrane vibration is about 0.3 nm.

Active versus passive cochlear biomechanics

If the cochlea were simply a fluid-filled tube (the coiling does not affect the physics), the amplitude evoked by a sound on the basilar membrane would be highly damped down. Such ‘passive’ cochleas are indeed the type studied by von Békésy and would now be classified as exhibiting severe sensorineural hearing loss. Both psycho-acoustics and auditory nerve recording in vivo lead one to expect much higher degrees of frequency selectivity. Vibration in the cochlear partition is intrinsically damped down by viscous forces, originating in part from the fluid within the duct and in part from viscous forces from within the organ of Corti. Extensive studies from a variety of animal models show that in vivo the basilar membrane amplitude is enhanced by over 100 times (i.e. by 40 dB) at low sound levels (for a review, see Robles and Ruggero4). The removal of the viscous damping forces requires a power input to the biomechanics and this is often described by saying that the cochlea is ‘active’. The problem was identified by Gold in 19486, but resisted elaboration until the instrumentation improved. The underlying cellular mechanisms have only become clearer over the past decade. The source of active amplification is, with little doubt, the cochlear outer hair cells. For each input sound frequency, a cluster of about 300 outer hair cells amplify the basilar membrane vibration, a process named ‘cochlear amplification’7.

Although traceable to Helmholtz in the 1860s, the idea that every section of the cochlea might behave like a lightly damped mechanical resonator went out of fashion in the early modelling attempts, as the propagating nature of the basilar membrane travelling wave was emphasised. The high damping in the cochlear duct was also seen as an insurmountable impediment to an explanation of cochlear tuning that depended on the mechanical properties of the cochlear cells even thought the literature contained suggestions to the contrary8. The advent of better measurements and clear improvement of cochlear preparation techniques re-opened this question and focused interest on mechanisms by which viscous damping could be reduced9. The dominant view now is that the outer hair cells both detect and feed forces back into the cochlear partition so that the frequency selectivity is essentially a property of the mechanics of the cochlea.

With the inclusion of outer hair cell forces, computer models can be made which match quite well measurements made with laser-based motion detection systems. More recently, there has been a revived interest in the cochlea as a two dimensional structure3,5. This work shows that a complete model of the cochlea may also have to pay attention to the variation of mechanical properties across the partition as well as along it. As is known from auditory nerve recordings10, the relative sharpness of tuning (on a logarithmic frequency scale) varies along the length of the cochlea, with the basal tuning curves being sharper than those at the apex.

Converting sound into electricity: mechano-electric transduction

At each site along the cochlea, the basilar membrane motion is signalled to the auditory nerve by the primary sensory cells of the cochlea, the inner hair cells. The primary cellular event is the deflection of the hair cell bundle. Such deflections occur at the same rate as the sound frequency and hence a primary requirement is that the mechano-electrical transduction step is rapid. In channel language, the transduction channel gating is too fast to involve intermediate biochemical steps.

Despite considerable effort, the molecular identity of the transducer in mammalian cochlear hair cells is unknown. This must represent one of the key unsolved problems of the cellular mechanisms of hearing. It is certainly associated with apical stereocilia (as reviewed recently by Gillespie and Walker11). It seems increasingly clear that the transducer mechanism is a complex of proteins, containing linkage and anchoring subunits. The functional assay for any potential candidates, normally so simple for ligand gated receptors, is complicated by this complexity. Most of the information about hair cell transduction is derived from much simpler model systems, particularly in lower vertebrates such as the frog and the turtle. By far the largest body of biophysical information about the mammalian transducer is derived from early stage (mainly postnatal days 0–8) mouse cochlear explants where the stimulus can be applied directly to the hair cell bundle12,13). There are few biophysical recordings from hair cells in the adult mammalian cochlea and this is a serious gap in the data. The technical reasons are not clear, although it is possible that the mature hair cell transducer requires factors that are hard to duplicate under in vitro recording conditions. Although there has been recent progress in recording from adult vestibular cells in the mouse14, there may be differences between auditory and vestibular transduction mechanisms. Although vestibular cells adapt, sensory hair cells within the cochlea contain channels modified for ultrafast response times and show little adaptation. Whether this means that different hair cell types differ in their transducer channel remains an open question.

A number of possible candidates for the transducer have been identified in other systems. In the nematode worm, a cluster of degenerin genes has been implicated in mechanosensitivity, but as yet no mammalian homologues have been convincingly shown to act as mechanically gated channels15. In the fruitfly, loss of bristle mechanosensitivity has been associated with mutations in the gene nompC (standing for no mechanoreceptor potential)16. This gene has generated a great deal of interest as it is a member of the TRP (standing for ‘transient receptor potential’) superfamily of membrane receptors that were originally identified in insect photoreceptors. This superfamily also contains a number of vertebrate stretch-sensitive proteins. The protein in the fruitfly is a transmembrane protein with a long C-terminal repeat of ankyrin binding sites. It is clear that mutations leading to deafness and hair cell loss are well worth exploring. There are recent examples where channel-like proteins, identified by genome searches, have shown considerable promise for the study of hearing17, but as yet the mammalian homologue of the mechano-electrical transduction channel has not been identified.

Converting electricity into sound: electromechanical transduction

The argument for an amplifying cell system in the cochlea depends on physics alone. The selectivity of the cochlea is greater than would be predicted from a knowledge of the materials and of the structure of the cochlea. The cochlea travelling wave would normally propagate along the basilar membrane under conditions where it would be highly damped by the viscosity of the cochlear fluid and of the organ of Corti. To overcome such dissipative forces, two alternative suggestions have been made.

The first originates with an idea that was first reported in 1985 when it was shown that turtle hair bundles undergo ‘active’ deflections18. There has been a recent revival of interest in the idea that the hair bundle is the source of cochlear amplification. In lower vertebrates, the bundle undergoes mechanical motions in excess of those induced by thermal fluctuations alone. Although this phenomenon was found originally in turtle hair cells, the more recent evidence comes from a re-investigation both in turtle19 and in frog hair cells20 of bundle forces that are generated when the stereocilia are pushed. Two mechanisms producing bundle motion have been described. The first is a force arising from the myosin-dependent motor responsible for tensioning of the tip link at the end of the stereocilia; this mechanism is unlikely to operate at frequencies above 100 Hz. The second is a consequence of calcium entering through the transducer channel, leading to channel reclosing and generating a force21. Both of these mechanisms are found in turtle hair cells, a system where the frequency range is limited to below about 700 Hz. The current discussion centres around whether either of these mechanisms can provide the right forces with correct bandwidth to contribute to mammalian hearing. The experimental evidence for either of these mechanisms operating in mammalian hair cells is not strong.

In the mammalian cochlea, the more probable cellular mechanism depends on the basolateral membrane of the hair cells. Reported in 1985 by Brownell and co-workers22, outer hair cells generate forces along their length when their membrane potential is altered. Although the original measurement was limited to relatively low frequencies to be captured at video rates, the use of patch clamp stimulating methods23 and the most recent techniques have shown that these length changes can be driven at frequencies in excess of 80 kHz24.

The hypothesis that outer hair cells can cancel viscous damping is supported by many pieces of experimental evidence. Outer hair cells are force generating elements that are stimulated by opening of the mechano-electric transducer channels in their apical pole. The cells are also positioned to feed back energy into the basilar membrane vibration. When outer hair cells are stimulated electrically in the intact organ of Corti, these forces are large enough to distort structures in the cochlear partition25.

The molecular basis of cochlear amplification

Given that the outer hair cell acts as a force generator, there has been considerable interest in the molecular nature of the force generating step. The cell's basolateral membrane exhibits properties that might be termed ‘piezo-electric’. The molecular basis for this force is a dense array of motor molecules in the basolateral membrane of the outer hair cells which are able to extract energy from the electric field across the membrane. This still remains a contentious issue, since the process has to operate at acoustic frequencies in excess of 10 kHz.

High resolution freeze-fracture studies show that the lateral membrane of outer hair cells contains a high density of particles about 8–11 nm in diameter with an estimated density in excess of 4000 per sq micron26,27. These lateral membrane particles can also be detected by electrophysiological signs, for when the membrane potential is changed there is a rapid transient current in the outer hair cell membrane that corresponds to a movement of charge28. This phenomenon is similar to the gating charges that can be detected when ion channels undergo a conformational change. However, the charge movement is larger by over an order of magnitude than can readily be seen in other cell types. In fact, the density is such that it can be measured in individual patches either as a charge movement or, equivalently, as a voltage-dependent capacitance of the membrane (since by definition of electrical capacitance, C = dQ/dV). Thus individual patches of membrane, explored with a patch pipette 1–2 µm in diameter, show both non-linear capacitance and movement29,30. For each of the 107 particles in the outer hair cell lateral membrane, between 1 and 2 electronic charges are required to transit through the membrane to account for the charge transient. The approximate match between the electrophysiology, the time course of the movement of the cell, and the observed freeze-fracture pattern in the outer hair cell membrane lead to the most economical explanation: that the particles form the ‘motor’ of the outer hair cell.

The simplest biophysical explanation for how the motor works is that it is an area motor26. When the membrane potential changes, each molecule undergoes a conformational change in the plane of the membrane. The high packing density ensures that a small change in protein area becomes a cell length change that can be observed under a microscope, since all the motors are in series. The area change need only be a few percent: this would theoretically be equivalent to a slight re-orientation of the molecule. It is also worth noting that an area change of the motor is likely to be intrinsically faster than a major structural re-organisation of the protein, as happens, for example, when an ion channel gates between open and closed states.

A recent significant advance has been the identification of a protein expressed in outer, but not inner, hair cells and which behaves like the predicted area motor31. A subtractive cDNA library was constructed by separating inner hair cells and outer hair cells and subtractively identifying genes expressed preferentially in outer hair cells. One of the 10 unique library clones identified was a 744 amino acid protein. When expressed in a kidney cell line, the protein exhibited the biophysical properties of a hair cell motor, conferring a (restricted) electromotility on the cells. It also conferred a voltage-dependent capacitance on the transfected cell, the second characteristic of the outer hair cell motor. The protein has been named ‘prestin’ in recognition of the speed of movement that outer hair cells possess. Subsequent protein analysis suggests that prestin contains 12 {alpha}-helices that form a hydrophobic core embedded in the membrane. Genomic analysis shows that prestin is the fifth member (SLC26A5) of an anion transporter superfamily SLC26 that includes a number of bicarbonate transporters expressed in the membranes of other epithelial systems32. On the basis of this family membership, prestin is likely to be a modified anion bicarbonate transporter. Therefore, the model is that, as part of its transport cycle, the protein is able to change its area.

A further step forward has been to combine electrophysiology and mutation analysis to suggest an economical explanation for prestin's ability to detect changes in the electrical field30. When prestin is mutated, by replacing charged with neutral amino acids, at sites around the hydrophobic core, major changes occur in the voltage dependence, but not to the charge movement. The voltage-dependent capacitance is, however, dependent on the presence of intracellular chloride in outer hair cells and in expression systems. An economical explanation is that the charge movement arises from the induced movement of intracellular anions into a deep pore of the protein structure on the cytoplasmic surface of the molecule. The motor thus appears to be a transporter that exhibits an incomplete transport cycle, but whose operation is exploited by the outer hair cell to generate a cellular force.

An earlier study using both immunohistochemistry and functional studies had suggested that the motor in outer hair cells had some affinities to a sugar transporter33,34. This result depends, in part, on the specificity of the antibody used. Surprisingly, there is more recent physiological evidence that members of the SLC26 family do transport other solutes. Thus prestin may share some properties of a sugar transporter. From the viewpoint of a cell biologist, the high density of this transporter in hair cells makes this an attractive system in which to study the interplay between molecular structure, cell function and system properties. As well as its growing interest to sensory physiologists, the cochlea thus has the potential to be a laboratory for testing proposals about how transport molecules work. When a mouse is made with the prestin gene ‘knocked out’, as it will undoubtedly be soon, then we will have much clearer view of prestin's contribution to auditory function.

Experimentally, outer hair cells removed from the cochlea can be stimulated to change length at frequencies in excess of 70 kHz. There has been a long-running debate about whether the membrane potential changes in the cells would be large enough at acoustic frequencies to activate the motor, since intracellular potentials will be attenuated by the cell's own low-pass electrical characteristics. For this reason it has been suggested that cochlear amplification could arise through the reaction of the hair cell stereocilia during deflection20. There must also be doubts about this scheme, as any stereocilial feedback force needs precise timing to work at any cochlear position. The resolution of this issue requires further experimental data on how adult mammalian hair cell mechanotransduction works.


   Channelopathies
Top
 Abstract
 Introduction
 Cochlear mechanics
 Channelopathies
Conclusions
 Key points for clinical...
 References
 
The cellular structure of the mammalian cochlea is well conserved between species, so that homologous populations of hair cells and supporting cells can be reliably identified. This has provided a basis for extrapolating between many animal systems (and in particular mouse models) and human hearing. There are differences of detail, however, which reflect the slightly different hearing ranges found between species. The region of the cochlea that seems to be most susceptible to insult is the basal end. At this end, cells have proved the most difficult to study. Data from several laboratories have indicated that there are also gradients of cell morphology and of channel species along the length of the cochlea that may correlate with selective hearing losses of both genetic and environmental origin.

Stereocilia and their associated transducer channels face into scala media, a high potassium and low calcium containing compartment. The K+ levels are maintained by active pumps in the stria vascularis that result in the efflux of K+ into scala media through a potassium channel that is also associated with the long QT syndrome in the heart (see Bitner-Glindzicz, this volume). Although the transducer channels themselves are intrinsically cation selective, they appear to be functional potassium channels as K+ is the majority cation that carries charge into the cell. K+ exits through the basolateral membrane of the hair cells and determines all changes of voltage in the cell. Potassium channels thus play a key role in the responses to sound.

Hair cell potassium channels

Inner hair cells have at least two distinct K+ channels in their basolateral membrane35 which together determine how the cell membrane potential responds to stereocilial deflection. In addition, inner hair cells express calcium channels (now characterised as an L-type calcium current) that are part of the triggering mechanism for synaptic release. Figure 1 summarizes a number of the known channel types found in mammalian hair cells.



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  		Fig 1. Main channel types in mammalian cochlear hair cells. Currents enter the cells through the mechano-electrical transducer channel in the stereocilia (st.) and are carried mainly by K+ ions. Channels gated by external ATP (a purinergic receptor P2X2) are distributed along the stereocilia. The currents exit at the hair cell base, through cell specific channels, near the nucleus, n. Inner hair cells (IHC) have two K+ channel types, a fast (IKf) and a slow (IKs) channel type35. Outer hair cells (OHC) have different, cochlear position-dependent sets of potassium channels as labelled (see text).

 
Outer hair cells have at least three types of K+ channel36. The main and novel outer hair cell current is carried through a channel that was originally termed IKn. It is active at negative potentials and serves to keep the outer hair cell hyperpolarised. This channel contains subunits of the KCNQ family of potassium channels. Other members of this family include KCNQ1, a channel expressed in the stria vascularis, and KCNQ2 and KCNQ3 which together form a channel that generates the M-current, an important modulatory potassium current of the CNS controlled by acetylcholine37. The hair cell member channel in this family is KCNQ4. This is a voltage gated potassium channel discovered only recently38,39. The channel is expressed prominently in outer hair cells and mutations result in a non-syndromic, autosomal dominant, progressive hearing loss (identified as one of the components of DFNA2 in humans). There is molecular and electrophysiological evidence to show that KCNQ4 expresses itself in a gradient along the cochlea40. The negative activation of IKn suggests that KCNQ4 may be acting in concert with some other, as yet undiscovered, subunit. One of the more intriguing questions is how this gradient (or indeed any cochlear gradient) might be set up. There is little indication of the answer, although there is evidence that channel properties in hair cells change during cochleogenesis41 and so a complex orchestration of changes of channel type occurs during development. Such gradients of channels are found throughout hearing organs. For example, there is a higher density of potassium channels expressed in outer hair cells from the basal coils of the cochlea42. The mammalian cochlea is not unique in this property, as other lower vertebrates show differential channel expression along the hearing organ. The turtle hearing organ depends on individual cells being electrically tuned, and differential expression of K+ channels provides the mechanism for the range of electrical tuning along the turtle's auditory organ43. However, there is no evidence for electrical tuning in the mammalian cochlea. The observed gradient must, therefore, reflect other features of cochlear function.

One of the curious receptor types found ubiquitously in the cochlea is a receptor for extracellular ATP. Such purinergic receptors have been found in a wide variety of tissues. They are cation channels and, in the cochlea, are localised on the apical (stereocilial) end of the cell44. Notably, non-sensory cells and basal cochlear hair cells express higher levels of the ATP receptor P2X2 than do apical cochlear hair cells. The gradient may be correlated with the larger transducer currents found in cells encoding higher frequencies, as the receptor is found on the stereocilia. The function of such purinergic receptors in the cochlea is unclear. ATP levels in the bathing endolymph appear to be very low. The higher expression level, experimentally, goes some way towards explaining why basal cells are experimentally more difficult to study since purinergic receptors, once activated by external ATP, are cation permeable. This may lead to calcium loading of the cells and consequent cell death.

Hair cell ligand-gated channels

Hair cells are under descending control from the central nervous system. A long-standing problem in cochlear physiology has been the precise role of the cholinergic efferent system: its behavioural effects appear to be subtle and hard to detect45. The medial component of the olivo-cochlear efferent pathway originates from cells near the lateral superior olive and terminates on the OHCs. A distinct branch terminates on the inner hair cell afferent terminals. There has been a long-running debate as to whether the efferents protect against noise damage46, or even enhance signals in a noisy background. Postnatal de-efferentation does not significantly alter cochlear development47. Molecular biological techniques have not clarified the efferent function role although they have identified the hair cell receptors. The receptor on outer hair cells for acetylcholine (ACh), liberated from the efferent terminals, is a novel one. It is now known to be composed of two subunits termed {alpha}9 and {alpha}10. It can be can be expressed as a functional channel in oocyte membranes48. It is highly permeable to calcium49,50. This permeability leads to the ACh-induced calcium rises that can be detected in outer hair cells51. Nevertheless, knockout of the {alpha}9 ACh receptor, the presumed OHC receptor, does not yield a phenotype showing major hearing abnormalities52. The possibility that the native ACh receptor is really not a homomer but a heteromer of two specialised cochlear receptor units, {alpha}9 + {alpha}10, leaves the case unsettled until the double knockout is performed. At the moment it is not known whether nature has already carried out this experiment for us and provided a mutation with the pathway functionally removed.

When the efferent pathway is activated, it releases ACh onto the outer hair cells. The action of acetylcholine thus can lead to opening of potassium channels and hyperpolarization of the cell membrane. The channel is presumed be the member SK2 of the small K channel family because of its sensitivity to apamin53. The channel is functional early in development54. Activation of the efferents produces a hyperpolarization and could serve to clamp OHCs at a hyperpolarized potential so removing outer hair cells from the feedback loop where they affect the mechanics. More subtle and slower effects of efferent activity can be detected as consequences of cytoskeletal alterations induced within the OHC55. There is likely to be much more activity in this field, as the ACh signalling pathway includes Rho and other small GTPases studied extensively by cell biologists56. Since these signalling molecules have already made an appearance in bundle morphogenesis, we can anticipate that the control pathways within the cell to maintain cochlear gain are going to become a good deal more complex that we appreciate at present.


   Conclusions
Top
 Abstract
 Introduction
 Cochlear mechanics
 Channelopathies
 Conclusions
Key points for clinical...
 References
 
Looking to the future is always hazardous. Looking back over the work on single cell physiology, considerable strides in understanding the cell biophysics have been made, but there are many nagging questions remaining about the precise distribution of membrane ion channels and transporters on hair cells and supporting cells. The outstanding question in the field in the identity of the hair cell transducer. There is no guarantee that its identification in a lower vertebrate system will answer the question of its identity in the mammalian cochlea. The issue in understanding mammalian hearing has been that the frequency range strains the measurement technology. However, one area that is emerging, driven in part by a desire to understand genomic complexity, is the development of large-scale computational frameworks in biology. These may allow a synthesis of molecular and cellular data into a systems model of the cochlea where the contribution of each part can be understood in the working of the whole.


   Key points for clinical practice
Top
 Abstract
 Introduction
 Cochlear mechanics
 Channelopathies
 Conclusions
 Key points for clinical...
References
 

  • The physiology of the cochlea needs characterisation before we understand the way in which specific mutations in cochlear proteins lead to hearing losses.
  • There is now little doubt that cochlear structure allows the inner ear to perform like a multichannel mechanical spectrum analyser.
  • The essential cellular components of this machine are now known and these are the targets for specific interventions in the future albeit, on a scale much smaller than found in current practice.


   Footnotes
 
Correspondence to: Prof. Jonathan Ashmore, Department of Physiology, University College London, Gower Street, London WC1E 6BT, UK


   References
Top
 Abstract
 Introduction
 Cochlear mechanics
 Channelopathies
 Conclusions
 Key points for clinical...
 References
 

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