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Outer Hair Cells and Electromotility

Jonathan Ashmore

University College London Ear Institute, London WC1X8EE, United Kingdom Correspondence: [email protected]

Outer hair cells (OHCs) of the mammalian cochlea behave like actuators: they feed energy into the cochlear partition and determine the overall mechanics of hearing. They do this by generating voltage-dependent axial forces. The resulting change in the cell length, observed by microscopy, has been termed “electromotility.” The mechanism of force generation OHCs can be traced to a specific protein, prestin, a member of a superfamily SLC26 of transporters. This short review will identify some of the more recent findings on prestin. Although the tertiary structure of prestin has yet to be determined, results from the presence of its homologs in nonmammalian species suggest a possible conformation in mammalian OHCs, how it can act like a transport protein, and how it may have evolved.

he outer hair cells (OHCs) of the mammali- frequency hearing. Although several extensive Tan cochlea are an identifiable group of cells reviews have been published (Ashmore 2008; of the inner ear, which are responsible for many He et al. 2014; Corey et al. 2017; Santos-Sacchi of the distinct features of our hearing (Fig. 1). et al. 2017), the emphasis here will be on a num- These features include absolute sensitivity to ber of outstanding issues. low sound pressure levels, selectivity to frequen- cies over many octaves, and the dependence ELECTROMOTILITY of cochlear performance on physiological status. These properties have collectively defined a The OHCs of the organ of Corti, the neurosen- process known as “cochlear amplification.” sory epithelium of the mammalian cochlea, are Although other orders of terrestrial animals organized in three (and sometimes four) rows also have cells homologous to the mammalian along the full length of the cochlear partition. www.perspectivesinmedicine.org OHCs, it seems that the evolution of hearing Viewing the cochlear partition in cross section organs has taken slightly different routes in dif- suggests that OHCs are placed in a position to ferent species. This review will focus specifically have the maximal mechanical influence on the on mammalian OHCs, their loss or functional flexure of the basilar membrane. failure being a major cause of hearing deficiency, The original observation that OHCs were including that caused by age. Thus, although cells that were “motile” was made by Brow- hair cells in all vertebrate species share com- nell and his coworkers in Geneva (Brownell et mon molecular features (see Köppl and Manley al. 1985). They showed, using intracellular re- 2018), there have been particular specializations cording electrodes, that the cells could be driven in mammalian hearing to enable and favor high- to change length when the membrane potential

Editors: Guy P. Richardson and Christine Petit Additional Perspectives on Function and Dysfunction of the Cochlea available at www.perspectivesinmedicine.org Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a033522 Cite this article as Cold Spring Harb Perspect Med 2019;9:a033522

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J. Ashmore

AB K+

Apical transducer

Prestin/ Transport SLC26A5

Basal synapses and K channels

10 µm

Figure 1. The elements of the mammalian outer hair cell (OHC). (A) An isolated OHC from turn 2 (∼5–10 kHz region) of the guinea pig cochlea. The apical stereocilia are apparent at the apical surface. (B) Schematic OHC showing the location of prestin/SLC26A5 down the basolateral surface, generating longitudinal forces. Transport + to regulate pHi is presumed to be collocated as a parallel property of prestin. K ions from scala media enter through the mechanoelectric transducer channels at the apex and exit through the basally located K+ channels. Both afferent (red) and efferent (blue) terminals are located at the base of the cell.

was changed. The term “electromotility” was from energy sources within the cell. A back-of- used as shorthand to describe this behavior the envelope calculation using the stiffness of and has stuck, even though it might imply that the cell shows that the maintenance of the cell “motile” means that the cells are migrating membrane potential at −50 mV allows suffi- somewhere. It required the widest electrical cient extraction of energy from the electric field www.perspectivesinmedicine.org bandwidth possible with patch clamp recording to explain the work done by the OHC against the to show that such length changes were rapid and mechanical constraints of the tissue in which certainly fast enough to claim that OHCs could they are embedded (Dallos 1991). be force-generating elements and are involved in Mammalian OHCs possess a very character- shaping cochlear mechanics at acoustic frequen- istic V-shaped bundle of stereocilia, serving cies (Ashmore 1987). Since then, a variety of to inject current into the cells when deflected. different biophysical techniques have shown As sensors of the movement of the basilar that the electromotile mechanism can be driven membrane, OHCs thus form part of a local me- over the full range of frequencies known to be chanical-electrical-mechanical feedback loop to encoded by most mammalian hearing organs, control basilar membrane tuning. The intimate and certainly up to 80 kHz (Frank et al. 1999). role of OHCs in such feedback has meant that It is strictly more accurate to describe the their function in the in vivo cochlea often has OHC as an “actuator” as the source of the energy to be interpreted by appeal to cochlear models. because the force generation derives from the When studied in isolation a property such as potential across the mechanoelectrical trans- electromotility gives an exaggerated impression ducer channels: it is not produced seemingly of the length change that an OHC may exhibit in

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Outer Hair Cells and Electromotility

a fully functioning cochlea. In vivo, when cells IDENTIFICATION OF THE MECHANISM are constrained by their surrounding cells, they operate more like force-generating elements. A number of hypotheses could explain the phe- A number of other features of OHCs should nomenon of OHC electromotility. There are also be considered when discussing electromo- several constraining observations: (1) the lateral tility. First, although they are neuroepithelial membrane of the OHC is packed with a particle cells specialized so that the apical surface facing about 8 nm in diameter; (2) a change in the scala media is mechanosensitive and the basal OHC membrane potential is accompanied by surface contains synaptic machinery, OHCs are a gating charge movement, or equivalently the relatively sparsely innervated by afferent fibers cell membrane capacitance is voltage dependent; in comparison to inner hair cells. It is clear that (3) the charge movement is blocked by the am- OHCs can generate activity in the type II audi- phiphilic anion salicylate (aspirin, with an addi- tory nerve fibers (Weisz et al. 2009), but this tional methyl group has the same effect); and information may be used in a very different (4) OHCs only acquire motile properties pro- way from the major sensory pathways from the gressively during a short period of development. sharply tuned type I fibers forming the majority The identification of prestin (Zheng et al. of the auditory nerve. Second, OHCs are the 2000) by using a subtracted complementary target of a descending pathway, the fibers of DNA (cDNA) library prepared from the mes- the medial olivocochlear bundle. These fibers, senger RNA (mRNA) of isolated hair cells in releasing acetylcholine (ACh), activate hetero- principle solves most of these problems. Mam- meric α9/10 AChRs on OHCs and serve to malian prestin is a 744 amino-acid protein with control the membrane conductance of the cell a predicted molecular mass of 81 kDa, and when (to K+). The net effect is to both hyperpola- it is expressed in heterologous cells they exhibit rize the cells and to reduce the amplitude of voltage-dependent movements and a nonlinear the receptor potentials in the cell and thus capacitance (NLC), which are indicative of pro- to reduce the mechanical OHC loop gain and tein rearrangements when under the influence overall cochlear sensitivity. The role of the effer- of the membrane potential. The surprise is that ent system is contentious but its effect on me- prestin is member of a superfamily of membrane chanical tuning (Murugasu and Russell 1996) transporters SLC26A5, a family whose other and distortion product emissions (e.g., Maison members are chloride-bicarbonate exchangers et al. 2007) is clear. There is also the suggestion, (Fig. 2) (Lohi et al. 2000). from studies in a mouse where the efferent cho- There are some differences in the behavior linergic receptor had been deleted, that the ef- of the NLC when it is studied in heterologous www.perspectivesinmedicine.org ferent system activity might even slow auditory cells (e.g., HEK293, TSA201, or CHO cells) and aging (Liberman et al. 2014). in isolated OHCs ex vivo. The difference seems

ABChloride Bicarbonate Compact Extended

14 TM helices in cell membrane

STAS domain in cytoplasm

Figure 2. Models for prestin. (A) Organization of prestin/SLC26A5 in the membrane as a monomer. Two mobile components of the protein are placed in the membrane (Gorbunov et al. 2014; Geertsma et al. 2015), whereas the carboxy-terminal region, containing the sulfate transporter and anti-sigma factor antagonist (STAS) domain is cytoplasmic (Mio et al. 2008). (B) Hypothetical model for coassembly into a tetramer. The carboxy-terminal region (red) forms a base against which the oligomer can deform, rapidly shifting between a compact (cell depolarized) and an extended configuration (cell hyperpolarized).

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J. Ashmore

2− − to depend on the molecular packing density: in can be detected as an electrogenic a SO4 :Cl cell systems where the prestin is expressed at a antiporter (the doubly charged sulfate ion being relatively low level (e.g., giving rise to a maxi- transported in place of two bicarbonates) mum NLC of 0.4 pF) corresponding to a copy (Schaechinger and Oliver 2007). Even though number of about 2.5 × 105 prestin molecules/cell mammalian prestin/SLC26A5 resembles an (equivalent to ∼100 prestins/μm2), the peak ca- antiporter for chloride and bicarbonate, it has pacitance is close to −75 mV (Oliver et al. 2001); proved more difficult to show that any transport in OHCs, the voltage at the peak progressively by the protein does occur. increases during maturation of the cell to reach a If other anions are used instead of chloride, steady state at −40 mV in the mouse at P12, then transport can be measured either by elec- where the density in the OHC membrane is es- trical methods or by using the classical methods timated to be about 4000 prestins /µm2 (Oliver of radioactive ion uptake. Thus, cells transfected and Fakler 1999). with mammalian prestin take up 14C-formate as an ion, but at a rate that is only weakly inhibited by 10 mM salicylate, the inhibitor of NLC (Bai AN INCOMPLETE TRANSPORTER et al. 2009). How a transport protein could give rise to a mo- Electrophysiological studies have shown that tor was solved soon after the discovery of prestin mammalian prestin/SLC26A5 is electrogenic. with the proposal that prestin/SLC26A5 was Using similar methods as those used by an incomplete transporter (Oliver et al. 2001). Schaechinger and Oliver, exposure of prestin The idea is that the protein acts like a mecha- expressing CHO cells to a low chloride–high noezyme as part of its transport cycle, but that bicarbonate gradient produces a change in the cycle is incomplete. As a result of binding of the membrane potential compatible with a 2:1 − − an intracellular anion (choride) the conforma- HCO3 :Cl stoichiometry (Mistrik et al. 2012). tional change in the protein is sufficient to It can also be shown, using a form of prestin produce a length change in the plane of the tagged with the fluorescent pH sensor pHluorin membrane and hence in the length of the to monitor the influx near the membrane, that OHC. The maximum electromotile change in the presence of prestin in the cells allows for a an OHC is 4%, so the change in the particle faster recovery from an acid load by allowing an diameter would be 0.04 × 8 nm = 0.3 nm, not influx of bicarbonate. impossibly small but close to the limit currently Although comparable experiments have not observable by structural techniques such as x- been completed fully to monitor choride, a ray crystallography or cryoelectron microscopy. movement of chloride movement can be detect- www.perspectivesinmedicine.org ed using yellow fluorescent protein (YFP), which is chloride sensitive, when the cells ANTIPORTER ACTIVITY are exposed to low (6 mM) chloride and high Prestin homologs have been detected in every (23 mM) bicarbonate on the outside favoring vertebrate hair cell wherever they have been exchange. An anion transport current can be looked for (He et al. 2014). None of the non- detected, however, with the much more perme- − mammalian cells, however, show the same de- ant anion thiocyanate, SCN (Schanzler and − − gree of electromotility as OHCs, although chick Fahlke 2012). Both SCN and Cl give rise to hair cells exhibit a limited degree of motility comparable NLC in transfected HEK293 cells, − − (Beurg et al. 2013). In chick and in zebrafish, although replacing external Cl with SCN the prestin homologs clearly act like transport- shifts the peak of the NLC curve more negatively ers for anions (Schaechinger and Oliver 2007). from −69 mV (typical of a cell expression system) In both these species, although in different to −102 mV. The authors conclude, however, orders, transport is electrogenic, with two bicar- that there is a transport pathway for anions and, bonates being exchanged for one chloride and on the basis of parallel studies with zSLC26A5 currents are readily observable. The transport (from zebrafish) and hSLC26A7 (from human),

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Outer Hair Cells and Electromotility

a pathway that may be conserved between many ed from these mice are nonmotile and that there members of the SLC26 family. is a 40–60 dB loss of cochlear sensitivity in vivo − Although SCN is used as permeant anion (Liberman et al. 2002). A cochlear microphonic in many transport studies, its transport pathway could still be measured so the OHC transduc- in prestin may differ from that of chloride (Bai tion was not affected, although there appeared et al. 2017). In a tet-inducible, prestin-express- to be a progressive apoptosis of the cells. A more ing human embryonic kidney (HEK) cell line, direct measurement of basilar membrane mo- which shows a large NLC, a current carried by tion in the hook region (60–70 kHz) of the chloride is also present whenever the NLC can cochlea also showed that the sharp mechanical be measured. Such observations only become tuning characteristic of the wild types was apparent with high expression levels, and so absent in the prestin knockout mouse but, curi- possibly have been missed in early experiments ously, did not show a significant threshold loss (where the peak NLC was 10%–15% of what can (Mellado Lagarde et al. 2008). The possible now be achieved). The evidence presented sup- explanation is that prestin contributes to the ports the idea that chloride is able to pass stiffness of the OHCs, and that removal of through a separate pathway intimately linked prestin alters the coupling of sound to basilar to the NLC, and most probably linked to a membrane mechanics. stretch-sensitive chloride channel reported for The issue of possible changes in the me- prestin (Rybalchenko and Santos-Sacchi 2003). chanical properties of the OHCs can be circum- Other members of the SLC26 family (SLC26A3 vented by using a prestin mutant mouse where and SLC26A6), as well as some ion channels two residues are substituted near the presumed (manifesting as a so-called omega or gating- last transmembrane helix (V499G and Y501H), pore currents [Moreau et al. 2015]), also show yielding OHCs that are structurally and bio- evidence for a similar sensitive leakage current. physically near normal but have an NLC shifted Whether this influences the gain and function of very positively and outside the physiological OHCs in cochlea mechanics is undecided, but it operating range (Dallos et al. 2008). In this does suggest that there may be several osmo- mutant indeed, the basilar membrane is no regulating mechanisms present in the cell. longer sharply tuned and there is a reduction in both frequency selectivity and cochlear sensi- tivity, which are the major consequences with PHARMACOLOGY no assumed alterations in cochlear impedance The pharmacological manipulations of prestin matching (Weddell et al. 2011). have suffered from a shortage of reagents. The www.perspectivesinmedicine.org best known is salicylate, which is effective at mM GENETICS: HUMAN HEARING levels from the extracellular surface, although the binding site is thought to be on the cytoplas- There has been some dispute about the preva- mic surface. Ingestion of aspirin is known to lence of prestin/SLC26A5 mutations in humans. (reversibly) elevate auditory thresholds (and lead An early report suggested that a single nucleo- to tinnitus as a consequence). As a competitive tide splice acceptor site mutation in the second antagonist to chloride, the dissociation constant intron of SLAC26A5 was responsible for a fi of salicylate is estimated from the NLC to be KD hearing de cit at the recessive DFNB61 locus =21µM. (Oliver et al. 2001). Nonsteroidal anti- (Liu et al. 2003). However, it was subsequently inflammatories have little or no effect. argued that this variation occurs no more fre- quently in the hearing impaired than in controls and therefore precludes a causative role (Tang GENETICS: MOUSE HEARING et al. 2005). In mouse, there is ample evidence that prestin To date, therefore, human prestin mutations determines cochlear sensitivity. The first knock- appear quite rare. A single case report identifies outs of prestin clearly showed that OHCs isolat- two profoundly deaf sisters with compound

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heterozygote mutations, one (p.W70X) in the tein, rather than in those regions assumed to amino-terminal region, which is expected to in- form the transmembrane loops (Franchini and activate the protein, and the other (p.R130S), Elgoyhen 2006). Predictions of adaptive changes which is within the sulfate transport motif of in such genes are based on whether there is a the SLC26 genes (Matsunaga and Morimoto sufficiently large synonymous versus nonsynon- 2016). In all other respects, the subjects were ymous ratio; by the same measure, it also ap- found to be normal. In a transgenic mouse mod- pears that the ACh α9 receptor, found in el for the latter mutation membrane, targeting OHCs, has also undergone adaptive evolution is impaired, kinetics are slowed (producing a in mammals, whereas pendrin (SLC26A4), reduced NLC at the measurement frequencies), also implicated in cochlear function, has not. and transport for thiocyanate is enhanced (Ta- It is not immediately clear functionally what kahashi et al. 2016). Apart from one other can- such changes in mammalian prestin indicate, didate mutation reported (p.R150Q) (Toth et al. although it is tempting to speculate that it is 2007), the p.W70X and the p.R130S are the only the modification to the carboxy-terminal “sul- deafness-causing mutations identified so far. fate transporter and anti-omega factor antago- nist” (STAS) domain that confers a special role. Within mammals there are examples of EVOLUTIONARY ASPECTS OF PRESTIN adaptive convergence in the auditory system. Is mammalian prestin really a modified trans- Some species of bat and all the toothed whales porter? SLC26A5 homologs have been found in use echolocation to find prey. All of these species a remarkably wide range of sensory hair cells use ultrasonic sounds with a matched require- both in chordates (He et al. 2014) as well as in ment to be able to detect such frequencies. invertebrates, for example, in the hearing organs Remarkably both dolphin and Doppler-sensi- of Drosophila melanogaster (Kavlie et al. 2015). tive CF bats exhibit what appears to be an exam- The conservation of SLAC26A5 suggests that it ple of convergent molecular evolution of prestin, has a particular role that has been conserved even though these animals have been separated through evolutionary changes and one sugges- phylogenetically for many tens of millions of tion is that it might play a role in controlling years (Liu et al. 2010). Four of these specific cellular pH or perhaps in the osmotic regulation convergent amino acid sites (G167S, I348T, of these cells. A565S, and E700D) are of particular interest There have been relatively few reports that as the latter two are in the STAS domain, sug- SLC26A5 gives rise to any form of hair cell mo- gesting this domain, which may play a special tility except in the mammals. Where they have role in the function of prestin. www.perspectivesinmedicine.org been studied biophysically, these prestin homo- logs in other species either seem to exhibit sig- STRUCTURE nificantly reduced NLC at acoustic frequencies, as for zebrafish prestin (Schaechinger and Oliver The structure of prestin remains unresolved. 2007), and/or are inserted into the membrane at The original sequence data suggested that the much lower levels than could generate motility, molecule had 12 transmembrane regions (Zheng as in chick hair cells (Beurg et al. 2013). What et al. 2000; Oliver et al. 2001). Other proposals, many of these homologs do exhibit, however, is including a model with 10 transmembrane ion transport. regions have been made (Bai et al. 2009). The As sequence data for the SLC26 super-fam- current best predictions for the structure, based ily became more common, and for SLC26A5 on homology modeling with the uracil transport in particular, bioinformatics revealed that family, suggest that there are instead 14 trans- there have been some significant evolutionary membrane domains with a duplication of a 7 changes. The main differences between mam- transmembrane motif (Gorbunov et al. 2014). malian and nonmammalian prestin are found Because the size of the particle in the OHC in the cytoplasmic portion of the resulting pro- lateral membrane is 8 nm in diameter, it is

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Outer Hair Cells and Electromotility

thus highly unlikely that prestin functions as a of the resulting particle is compatible with the monomer, but is oligomeric, most probably a images obtained by electron microscopy of the tetramer. Some compelling evidence for this OHC lateral membrane, but surprisingly about conclusion comes from single-molecule photo- 60% of the particle mass appears within the cell bleaching experiments. Successive bleaching of on the cytoplasmic surface of the membrane, green fluorescent protein (GFP) tagged prestin suggesting this is where the STAS domains are expressed in HEK reveals a series of equal assembled. It is therefore tempting to suggest amplitude steps that is most consistent with a that prestin is a dimer of dimers, with the cyto- tetrameric structure (Hallworth and Nichols plasmic STAS domain region perhaps forming a 2012). These results are compatible with earlier plate against which the membrane-bound units results that suggest that prestin, at least when distort. expressed in mammalian cell lines, acts as a high-order oligomer based on a stable dimer ORGANIZATION OF PRESTIN formed by disulfide bonds between single mol- IN THE LATERAL MEMBRANE ecules (Zheng et al. 2006). The amino acid sequence of prestin also pre- The high density of prestin in the OHC lateral dicts a cytoplasmic carboxy-terminal region, membrane is quite surprising. The packing is accounting for nearly 30% of the peptide, which tight so that the lateral membrane particu- contains a distinguishing STAS domain in com- late density covers about 60% of the surface. mon with other members of the SLC26 anion This high packing ensures that such molecular transporters. The role of this domain is unclear. crowding amplifies up any small changes in sur- The crystal structure of the cytoplasmic domain face area of the protein. Even so, to act as a is known both in mammals and in chick and force-generating element, it is necessary to en- there are subtle differences. The mammalian do- sure that the membrane does not buckle, thereby main contains an unanticipated anion binding allowing all force to be generated within the site that may act as a reservoir foranions involved plane of the membrane. OHCs have evolved a in the rapid conformational changes. In distinc- submembranous cortical network to ensure that tion, the chick homolog contains no such site. the membrane retains a degree of rigidity (Ka- Although there is not a full structure, with linec et al. 1992). transmembrane and STAS units together, for The question of how membrane-associated mammalian prestin, there is for a bacterial prestin links to the underlying cytoskeleton re- member of the SLC26 family. The structure at mains unresolved. The spacing between the 3.2 Å resolution of SLC26Dg, the facilitator (via plasma membrane and the cytoskeleton is about www.perspectivesinmedicine.org bicarbonate) of the proton-coupled fumarate 50 nm and, although structures linking the symporter from the bacterium Deinococcus two are often termed “pillars” and apparent gethermalis reveals that this molecule forms an in electron micrographs (Holley et al. 1992), obligate dimer (Geertsma et al. 2015). The di- the nature of the linkage is unknown. The puzzle meric feature is shared by all members of the is that the prestin-related particles outnumber SLC26 family and the NLC evidence based on the pillars by an order of magnitude. A particu- independent manipulation of the two compo- lar form of spectrin, βV, forms cytoskeletal nents suggest that the two units do not function meshwork with actin, and further builds up independently (Detro-Dassen et al. 2008). Thus, as prestin levels rapidly increase during early structural studies need to identify the nature of postnatal development (Legendre et al. 2008). interface between the component proteins. Although spectrin βV interacts directly with In support of this proposal, the most com- F-actin and band 4.1, it does not interact with plete image of the mammalian prestin is ob- prestin. Interestingly, an unidentified compo- tained by negative staining of prestin particles nent in lysates derived from mature auditory and reconstruction with a fourfold symmetry at organs does promote a prestin–spectrin interac- a resolution of 2 nm (Mio et al. 2008). The size tion, whereas lysates from other tissues do not.

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It has been suggested that the spectrin βV iso- has so far not been addressed. A number of form, like that of prestin itself, has undergone studies have endeavored to identify the “motor” adaptive evolution from a form involved in a motif by swapping motifs in prestin. A span molecular trafficking network, to one that allows of 11 amino acids (158–168) near the sulfate it to provide the molecular support for the OHC transport motif swapped into nonmammalian mechanisms (Cortese et al. 2017). orthologs is sufficient to confer NLC and motor properties in cells transfected with such modi- fied proteins (Tan et al. 2012). Further chimeric CONCLUDING REMARKS prestins have been constructed, containing se- There is sometimes a perception that we now quences from both mammalian and nonmam- have a molecule that can be assigned the role malian prestins, which show both characteristics of a molecular motor that drives electromotility of NLC and of transport (Schaechinger et al. in OHCs, and that all is solved. Although it is 2011). true that many of the low hanging fruits have A number of fundamental biophysical been picked, there remain a number of out- challenges in cochlear neurobiology arise from standing questions. hearing performance at the upper end of the The first is the so-called RC time constant auditory range. What sets the upper limit to problem that arises because the membrane of an mammalian hearing? Is it the maximum oper- OHC has an electrical filtering effect on any ating frequency of the hair cell transduction changes in the membrane potential driving the channels? Or is it a structural problem of how prestin. Although many ingenious solutions to evolve a sufficiently high-frequency cochlea? have been proposed (see Corey et al. 2017), it Or is it that the feedback loop we have discussed has proved remarkably difficult technically to above has an inherent bandwidth, traceable in study OHCs from the basal high-frequency part to the properties of prestin/SLC26A5? end of the cochlea. Not only are electrical re- Some of the answers depend on developing tools cording bandwidths limited (for patch clamp to explore ultrafast structural processes. For that, systems to below 10 kHz), but basal hair cells the prestin/SLC26A5 system provides a useful have proved difficult to handle. A partial answer, laboratory. however, may be that basal hair cells have a high ionic channel density, mainly of the Kv7.4 chan- nel, and therefore a small electrical time cons- ACKNOWLEDGMENTS tant (Johnson et al. 2011). It also seems likely that OHCs are not driven exclusively by intra- The work is supported by grants from the Med- www.perspectivesinmedicine.org cellular potentials, but by transmembrane po- ical Research Council (MRC) (MR/K015826), tential (Mistrik et al. 2009) and so the space Biotechnology and Biological Sciences Research around the OHCs in the organ of Corti becomes Council (BBSRC) (BB/M00659), and the Royal an essential aspect of their function. Society. The molecular basis for the actuator behav- ior of prestin/SLC26A5 remains unclear, al- though inasmuch as all transporters can be REFERENCES considered as mechanoenzymes, a conforma- ÃReference is also in this collection. tional change of the molecule with a component acting in the plane of the membrane seems to Ashmore JF. 1987. A fast motile response in guinea-pig outer hair cells: The cellular basis of the cochlear amplifier. be the correct starting point. The reason for J Physiol 388: 323–347. the current uncertainty is that the molecular Ashmore J. 2008. Cochlear outer hair cell motility. Physiol structure of prestin remains unresolved. It clear- Rev 88: 173–210. Bai JP, Surguchev A, Montoya S, Aronson PS, Santos-Sacchi ly seems to form a tetrameric molecule in the ’ fi J, Navaratnam D. 2009. Prestin s anion transport and membrane, but how it is traf cked and how the voltage-sensing capabilities are independent. Biophys J interfaces between the monomers are formed 96: 3179–3186.

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Outer Hair Cells and Electromotility

Jonathan Ashmore

Cold Spring Harb Perspect Med 2019; doi: 10.1101/cshperspect.a033522 originally published online September 4, 2018

Subject Collection Function and Dysfunction of the Cochlea

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