Учебники / Auditory Trauma, Protection, and Repair Fay 2008

the basolateral membrane of strial marginal cells via the Na+/2Cl−/K+ cotransporter SLC12A2 and the Na+/K+-ATPase ATP1A1/ATP1B2 and secreted across the apical membrane into endolymph via the K+ channel KCNQ1/KCNE1 (Wangemann et al. 1995a; Shen et al. 1997). Na+ and Cl− taken up together with K+ via the Na+/2Cl−/K+ cotransporter SLC12A2 are recycled in the basolateral membrane via the Na+/K+-ATPase and Cl− channels CLCNKA/BSND and CLCNKB/BSND that are associated with BSND (Barttin).

The pathway of K+ through stria vascularis and through the hair cells is well established. In contrast, two concepts are promoted for the pathway from perilymph toward spiral ligament. One concept envisions that K+ enters perilymph and flows through perilymph toward spiral ligament. This concept is supported by flux and current measurements (Zidanic and Brownell 1990; Salt and Ohyama 1993). The other concept envisions that K+ released from the hair cells never enters perilymph but is taken up by adjacent supporting cells and funneled from cell to cell via a gap junction network toward the spiral ligament (Spicer and Schulte 1996). This concept is based on an interesting, but unproven, hypothesis derived from the finding of gap junctions and KCl transporters in supporting cells of the organ of Corti. The transport direction of KCl transporters, however, is outwardly directed given the usual stoichiometry and ionic gradients, which precludes their involvement in the uptake of K+ (Warnock and Eveloff 1989; Adragna et al. 2004). Further, if the gap junctions GJB2 or GJB6 would be required for K+ cycling, a disruption of K+ delivery to stria vascularis and a collapse of scala media would have been expected in mice that lack these gap junction proteins (Cohen-Salmon et al. 2002; Teubner et al. 2003). The fact that no collapse was seen in mice lacking GJB2 or GJB6 argues against this concept that GJB2 or GJB6 are essential for K+ cycling.

K+ cycling in the cochlea is not limited to the loop through the sensory cells. Part of the current that is generated by stria vascularis is carried through outer sulcus cells and through Reissner’s membrane (Konishi et al. 1978; Zidanic and Brownell 1990; Salt and Ohyama 1993). The significance of these parallel current loops may lie in the opportunity to fine tune the current through the sensory hair cells. Currents through Reissner’s membrane are carried by Na+ (Lee and Marcus 2003) and currents through outer sulcus epithelial cells are carried by K+ and Na+ (Marcus and Chiba 1999; Chiba and Marcus 1992).

K+ cycling does not only occur in the cochlea but also in the vestibular labyrinth (Wangemann 1995). Endolymphatic K+ flows into the sensory hair cells via the apical transduction channel and is released from the hair cells via basolateral K+ channels (Valli et al. 1990). Fibrocytes connected by gap junctions including GJB2 may be involved in delivering K+ to vestibular dark cells (Kikuchi et al. 1995). Extracellular K+ is taken up into vestibular dark cells via SLC12A2 and ATP1A1/ATP1B2 (Marcus et al. 1987; Wangemann 1995). To conclude the cycle, K+ is released into endolymph via the K+ channel KCNQ1/KCNE1 (Marcus and Shen 1994).

Cochlear fluid homeostasis requires a well tuned balance between K+ secretion and K+ reabsorption. Failure to maintain this balance will result in

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an enlargement of the endolymphatic compartment as seen in Menière’s´ disease and Pendred’s syndrome or result in a collapse of scala media as seen in Jervell– Lange-Nielsen syndrome. K+ secretion by strial marginal cells and vestibular dark cells is sensitive to the basolateral K+ concentration. Even small millimolar changes in the basolateral K+ concentration alter the rate of K+ secretion (Wangemann et al. 1995a; Wangemann et al. 1996b). It appears that the K+ secretory cells are sensors for K+ rivaling the exquisite sensitivity of the plasma K+ sensor in the adrenal cortex that governs the release of aldosterone and thereby K+ excretion in the kidney. The sensitivity of K+ secretory cells in the cochlea and vestibular labyrinth ensures that K+ does not accumulate in perilymph or in the intrastrial fluid space, which, in the vestibular system, would interfere with neuronal transmission and, in the cochlea, would interfere with the generation of the endocochlear potential.

K+ cycling is subject control by acoustic stimulation. Intense acoustic stimulation causes a temporary threshold shift, reduces the endocochlear potential and endolymphatic K+ concentration and alters the K+ efflux pathway from endolymph to perilymph (Salt and Konishi 1979; Thorne et al. 2004). Sound stimulation releases ATP into cochlear fluids (Munoz et al. 2001). ATP is not only an energy equivalent but also a paracrine messenger. ATP released into perilymph reaches P2X receptors in the organ of Corti and reduces outer hair cell motility, which dampens the cochlear amplifier (Housley et al. 1999; Zhao et al. 2005). ATP released into endolymph stimulates P2X receptors in Reissner’s membrane and the apical membrane of outer sulcus (King et al. 1998; Lee et al. 2001). P2X receptors are nonselective ion channels that in concert with basolateral K+ channels support transcellular effluxes of K+ from endolymph to perilymph. These cation effluxes generate currents that are parallel to the transduction current through the hair cells and effectively reduce the current density through the sensory hair cells. ATP released into endolymph activates not only P2X receptors but also P2Y4 receptors located in the apical membrane of strial marginal cells (Sage and Marcus 2002). P2Y4 receptors are G-protein- coupled receptors that reduce K+ secretion across the apical membrane of strial marginal cells via protein kinase C-mediated phosphorylation and inhibition of the apical K+ channel KCNQ1/KCNE1 (Marcus et al. 2005). A reduction in K+ secretion can be expected to reduce the endocochlear potential and thereby the driving force for sensory transduction. A similar protective mechanism has been observed in the vestibular labyrinth. ATP inhibits K+ secretion in vestibular dark cells via activation of apical P2Y4 receptor and activates parallel current loops via activation of P2X receptors in the apical membrane of vestibular transitional cells (Liu et al. 1995; Marcus et al. 1997; Lee et al. 2001).

K+ cycling is also subject to systemic stimulation. Physical and emotional stresses leading to increased norepinephrine and epinephrine plasma levels enable a number of organ-specific responses that are mediated by -adrenergic receptors and support a “fight–or-flight” reaction. For example, 1-adrenergic receptors increase heart rate and force and 2-adrenergic receptors open and moisturize airways and eyes. 1-adrenergic receptors have been found in the organ of Corti,

in the outer sulcus, and in stria vascularis (Fauser et al. 2004). 1-Adrenergic receptors in stria vascularis and vestibular dark cells stimulate K+ secretion via an increase in the cytosolic cAMP concentration (Wangemann et al. 1999, 2000). In addition, 2-adrenergic receptors have been identified in the spiral ligament (Schimanski et al. 2001). Acceleration of K+ cycling in the inner ear may be part of the preparation for a successful “fight-or-flight” reaction.

5.2 pH and HCO−3

The pH of cochlear endolymph of 7.5 is higher than the pH of perilymph (pH 7.3) or plasma (Wangemann et al. 2007). Similar observations have been made in the vestibular labyrinth (Nakaya et al. 2007). The higher pH of endolymph is consistent with a higher concentration of HCO−3 , 31 versus 20 mM in perilymph (Sterkers et al. 1984; Ikeda et al. 1987c) (Fig. 3.7). The endolymphatic pH depends on H+ and HCO−3 secretion and on carbonic anhydrase activity (Sterkers et al. 1984; Ikeda et al. 1987c; Stankovic et al. 1997). Mechanisms of endolymphatic HCO−3 homeostasis are not yet fully understood, but it is conceivable that the endolymphatic HCO−3 concentration is maintained by secretory and absorptive mechanisms. Sites discussed for HCO−3 secretion are spiral prominence and outer sulcus epithelial cells as well as spindle cells of stria vascularis that contain the Cl−/HCO−3 exchanger SLC26A4 (pendrin) in their apical membrane (Wangemann et al. 2004, 2007). Sites that may be engaged in the absorption of HCO−3 may include the interdental cells of the spiral limbus. It is conceivable that HCO−3 , which originates from metabolically generated CO2, is cycled through endolymph before being eliminated from the cochlea via the capillary beds in stria vascularis, spiral ligament and spiral limbus. Support for this cycling of HCO−3 comes from the observation that acoustic stimulation, which increases stria metabolism and CO2 production, causes an alkalization of endolymph (Ikeda 1988).

The importance of pH homeostasis of the cochlear fluids is linked to cochlear function via the general pH sensitivity of ion channels, transporters, and metabolic enzymes. For example, Ca2+ absorption from endolymph via TRPV5 and TRPV6 Ca2+ channels is inhibited in Pendred syndrome, which is associated with an acidification of endolymph (Nakaya et al. 2007; Wangemann et al. 2007). Further, experimental maneuvers that cause acidification of cochlear fluids including inhibition of carbonic anhydrase, application of acidic fluids to the round window or flushing the round window membrane with CO2 gas, have been shown to reduce the endocochlear potential (Sterkers et al. 1984; Ikeda et al. 1987c; Ikeda and Morizono 1989a,1989b). These short-term effects of an acidic pH may become detrimental under long-term conditions. Application of acidic fluids to the round window has been shown to be detrimental by enhancing free radical stress mediated hearing loss induced by platinum containing anticancer drugs whereas application of alkaline fluids has been shown to have a protective effect on hearing (Rybak et al. 1997; Tanaka et al. 2004). Consistently, some forms of systemic acidosis and impairment of cochlear

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pH regulation by mutations of essential subunits of H+-ATPases, mutations of Cl−/HCO−3 exchangers SLC26A4 (pendrin) and the Na+/HCO−3 transporter SLC4A7 are associated with hearing loss (Karet et al. 1999a; Everett et al. 2001; Stover et al. 2002; Bok et al. 2003). It is conceivable that long-term effects of fluid and tissue acidosis are potentiated by promoting the generation of free radicals and activation of the innate immune system (Lardner 2001; Kellum et al. 2004).

5.3 Ca2+

Endolymph is not only an unusual extracellular fluid for its high K+ and low Na+ concentration but also for its low Ca2+ concentration. Endolymph contains 20 μM Ca2+, which is very low compared to other extracellular fluids such perilymph or plasma, which contain 1–2 mM Ca2+ (Bosher and Warren 1978; Ninoyu and Meyer zum Gottesberge 1986a; Ikeda et al. 1987d; Salt et al. 1989) (Fig. 3.7). Ca2+ enters the hair bundle together with K+ and is necessary for the generation of the mechanoelectrical transduction current (Ohmori 1985; Lumpkin et al. 1997; Ricci and Fettiplace 1998). In addition, Ca2+ is responsible for fast (milliseconds) and slow (tenth of milliseconds) adaptations of the transduction mechanism (Holt and Corey 2000). Ca2+ that enters the hair bundle via the transduction channel is removed from the cytoplasm of the stereocilia by the Ca2+-ATPase PMCA2 (Apicella et al. 1997; Yamoah et al. 1998).

For normal auditory function, the endolymphatic Ca2+ concentration can neither be too low nor too high. Elevated Ca2+ concentrations block transduction and the generation of microphonic potentials but reduced Ca2+ concentration suppress microphonic potentials as well (Tanaka et al. 1980; Marcus et al. 1982; Ohmori 1985; Ricci and Fettiplace 1998). Pathologically low endolymphatic Ca2+ concentration have been found in deaf-waddler mice and are suspected to be the cause of deafness (Wood et al. 2004a). Reduced endolymphatic Ca2+ concentrations are also suspected to be the cause for hearing loss associated with vitamin D deficiency and hypoparathyroidism, two conditions that are associated with low plasma Ca2+ concentrations (Brookes 1983; Ikeda et al. 1987a, 1987b, 1989). Conversely, elevated endolymphatic Ca2+ concentrations are thought to contribute to hearing loss in the guinea pig model of Ménière’s disease (Ninoyu and Meyer zum Gottesberge 1986b), to transient threshold shifts following acoustic overstimulation (Ikeda and Morizono 1988), and to failure to aquire hearing in a mouse model of Pendred’s syndrome (Wangemann et al. 2007).

Ca2+ absorption from endolymph appears to be driven at least in part by the endocochlear potential since the endolymphatic Ca2+ concentration is somewhat correlated with the magnitude of the endocochlear potential (Ikeda et al. 1987d). In analogy to Ca2+ absorption in proximal and distal tubules of the kidney, it is conceivable that Ca2+ absorption occurs partially through paracellular and partially through transcellular mechanisms. Transcellular pathways include uptake of Ca2+ across the apical membrane via TRPV5 and TRPV6 channels, buffering of Ca2+ in the cytosol by Ca2+ binding proteins and export via basolateral Ca2+-ATPases (Yamauchi et al. 2005; Nakaya et al. 2007; Wangemann et al. 2007).

Ca2+ homeostasis in cochlear endolymph has long been assumed to involve active Ca2+secretion based on the finding that the endolymphatic Ca2+ concentration is higher than what would be predicted for passive distribution across a semipermeable barrier. The finding that vanadate, an inhibitor of Ca2+-ATPases, reduced the endolymphatic Ca2+ concentration more than would be predicted from the inhibition of the endocochlear potential suggested that vanadatesensitive Ca2+-ATPase are responsible for Ca2+ secretion into endolymph (Ikeda and Morizono 1988). This concept has been refined by the finding of very low endolymphatic Ca2+ concentrations in the deaf-waddler mouse, which bears a loss-of-function mutation in the PMCA Ca2+-ATPase ATP2B2 (Street et al. 1998; Konrad-Martin et al. 2001; Wood, et al. 2004b).

6. Generation of the Endocochlear Potential

The endocochlear potential is generated by stria vascularis and provides the main driving force for sensory transduction in the organ of Corti (von Békésy 1950; Davis 1953; Wangemann and Schacht 1996; Wangemann 2002). Stria vascularis is functionally a two-layered epithelium consisting of the strial marginal cell layer, which provides a barrier between endolymph and intrastrial fluid and the basal cell layer that provides the a barrier between interstrial fluid and the extracellular fluid spaces in spiral ligament that are in open contact with perilymph (Fig. 3.8). Strial intermediate cells are functionally a part of the basal cell barrier, as they are connected to basal cells via a high density of gap junctions (Kikuchi et al. 1995). The endocochlear potential is essentially a K+ equilibrium potential that is generated by the KCNJ10 K+ channel located in the intermediate cells of stria vascularis in conjunction with a very low K+ concentration in the intrastrial fluid spaces and a normal high K+ concentration in the cytosol of intermediate cells (Takeuchi et al. 2000; Marcus et al. 2002). The endocochlear potential can be measured across the basal cell barrier, as intermediate cells are functionally a part of the basal cell barrier (Salt et al. 1987). Strial marginal cells contribute to the generation of the endocochlear potential in that they keep the K+ concentration in the intrastrial fluid spaces low (Wangemann et al. 1995a). Similarly, spiral ligament, which consists of a large network of interconnected fibrocytes that are endowed with uptake mechanisms for K+, contributes to the endocochlear potential in that it assists in maintaining the high cytosolic K+ concentration in the intermediate cells.

7. Homestatic Disorders

Cochlear homeostasis is critical for all aspects of sensory transduction. Consequently, dysfunction of homeostatic mechanisms is a main cause of deafness (Fig. 3.9). Many hereditary forms deafness, including the most frequently occurring forms, as well as acquired forms of hearing loss, are due to failures to maintain cochlear homeostasis. These include connexin-related deafness,

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Figure 3.9. Overview of homeostatic disorders. Dysfunction of genes that are expressed in the lateral wall, the organ of Corti or the spiral limbus cause deafness due to failure to maintain cochlear homeostasis.

Pendred syndrome, Jervell–Lange-Nielsen syndrome, Bartter syndrome, renal tubular acidosis with sensorineural deafness syndrome, and Ménière’s disease.

7.1 Connexin-Related Deafness

Most cells in tissues are connected among each other by gap junctions to coordinate their behavior through electrical coupling and the exchange of metabolites and second messengers. Examples of cochlear cells that are interconnected by gap junction include supporting cells of the organ of Corti, inner and outer sulcus epithelial cells, strial intermediate and basal cells, spiral ligament fibrocytes, Reissner’s membrane epithelial cells, and fibrocytes of the spiral limbus (Kikuchi et al. 2000). Exceptions to this rule are inner and outer hair cells and strial marginal cells. Gap junction are formed by docking two hemichannels expressed by adjacent cells. Each hemichannel consists of homoor heteromeric connexin proteins. Five connexins are most prominently expressed in the cochlea, GJB2 (Cx26), GJB6 (Cx30), GJA1 (Cx43), GJA7 (Cx45), and GJE1 (Cx29) (Ahmad et al. 2003).

Mutations of GJB2 (Cx26) are the most prevalent cause of nonsyndromic deafness in childhood accounting for about one-half of all cases (Kelsell et al. 1997; Zelante et al. 1997; Rabionet et al. 2000). Mutations of GJB2 are responsible for recessive as well as dominant forms of non-syndromic deafness (Denoyelle et al. 1998). GJB2 is widely expressed in the cochlea in particular in strial basal cells and spiral ligament fibrocytes as well as in supporting cells of the organ of Corti and in inner and outer sulcus epithelial cells (Kikuchi et al. 1995). It had been suggested that cells in the gap junction networks surrounding the bases of inner and outer hair cells take up K+ and funnel it toward K+ secretory cells in the lateral wall and hypothetical K+ secretory cells in the spiral limbus

(Kikuchi et al. 1995; Spicer and Schulte 1998). Gap junctions would thereby be essential for K+ cycling. Mice lacking expression of GJB2 from the organ of Corti (but not from lateral wall of the cochlea or from other organs) had a significant hearing loss and provided valuable insights into the role of gap junctions in the organ of Corti (Cohen-Salmon et al. 2002). The endocochlear potential was normal at the onset of hearing but failed to fully develop to adult levels, which is consistent with the observed hearing loss. The endolymphatic K+ concentration was normal at all ages suggesting that GJB2 is not essential for K+ cycling. The observed reduction in the endocochlear potential is likely due to a compromise in the epithelial barrier caused by progressive apoptosis of supporting cells in the organ of Corti that begins at the onset of hearing with the cells nearest to the inner hair cells. It is conceivable that GJB2 in these cells is essential for the sharing of metabolites (Matsunami et al. 2006). An import molecule, which is taken up by the cells nearest to the inner hair cells, is glutamate that is released from the inner hair cells in response to sound stimulation. Buffering of glutamate may depend on coupling between supporting cells, as glutamine synthase is mainly expressed in the neighbors of the cells that express the glutamate uptake transporter SLC1A3 (Eybalin et al. 1996; Ottersen et al. 1998). Consistent with glutamate toxicity as a key factor is the finding that gap junctions containing mutations of GJB2, which cause hearing loss, maintained ionic coupling but failed to exchange larger biochemicals (Zhang et al. 2005).

Mutations of GJB6 (Cx30) are another prevalent cause of nonsyndromic deafness in childhood (Del Castillo et al. 2003). GJB6 is expressed in a pattern similar to that of GJB2 (Lautermann et al. 1998). Mice that lack functional expression of GJB6 are profoundly deaf since they lack the endocochlear potential (Teubner et al. 2003). The endolymphatic K+ concentration, however, was normal at the onset of hearing although reduced later. Cells in the organ of Corti underwent massive apoptosis at the time when the endocochlear potential failed to develop. These results illustrate that GJB6 is required for the generation of the endocochlear potential but not essential for K+ cycling. Interestingly, loss of GJB6 (CX30) renders the capillaries in stria vascularis leaky to the intrastrial space (Cohen-Salmon et al. 2007). This leak provides an electrical short for the endocochlear potential. Generation of the endocochlear potential depends directly on the electrical coupling between intermediate and basal cells of stria vascularis, however, the chemical coupling between intermediate and basal cells of stria vascularis and spiral ligament fibrocytes may be equally important in that the connected cells may provide a buffer system HCO−3 , pH, free radicals, Ca2+, and metabolites. Differences in the quality of coupling of gap junctions that consist of GJB2 with or without GJB6 are now beginning to be understood (Sun et al. 2005; Zhao 2005). Nevertheless, a failure to buffer metabolites may be the cause for the pathologic leakiness of capillaries in stria vascularis that leads to a collapse of the endocochlear potential and to deafness in mice and patients lacking functional GJB6.

Mutations of GJA1 (Cx43) are also associated with non-syndromic deafness (Liu et al. 2001). GJA1 expression in the cochlea of adult mice is limited to

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the spiral ligament, capillaries of stria vascularis, and bone of the otic capsule (Cohen-Salmon et al. 2004). However, GJA1 is expressed in various cells of the developing mouse cochlea. The etiology of hearing loss is yet unclear.

Other connexins expressed in the cochlea are candidate genes for human deafness. GJA7 (Cx45), as shown for GJA1 (Cx43), is expressed in the developing mouse cochlea (Cohen-Salmon et al. 2004). Expression in the adult cochlea is limited to capillary endothelial cells. Whether mutations of GJA7 cause deafness is currently unclear. In contrast, mice lacking GJE1 (Cx29) are delayed in the maturation of hearing, have an early onset of a high-frequency hearing loss, and an elevated sensitivity to noise damage (Tang et al. 2006). The phenotype includes prolonged latencies of auditory brain stem responses which is consistent with the expression of GJE1 in Schwann cells that provide myelination of the soma and dendritic fibers of the spiral ganglion cells.

7.2 Pendred Syndrome

Pendred syndrome is the most common syndromic form of deafness. Pendred syndrome is an autosomal recessive disorder associated with sensorineural hearing loss, developmental abnormalities of the cochlea, and euthyroid goiter (Pendred 1896). Deafness in Pendred’s syndrome is generally profound although sometimes late in onset and provoked by stresses such as light head injury or infection (Cremers et al. 1998; Usami et al. 1999; Luxon et al. 2003). A positive perchlorate discharge test and an enlarged vestibular aqueduct appear to be the most reliable clinical signs of Pendred syndrome (Reardon et al. 2000). Vestibular dysfunction is uncommon. Goiter is variable and generally develops after puberty (Royaux et al. 2000).

The syndrome is caused by mutations of SLC26A4 (pendrin) (Everett et al. 1997). SLC26A4 is an anion exchanger that can transport Cl−, I−, and HCO−3 (Scott et al. 1999; Scott and Karniski 2000). In the cochlea, SLC26A4 is expressed in apical membranes of spiral prominence epithelial cells and spindleshaped cells of stria vascularis, in outer sulcus cells and root cells of the spiral ligament (Everett et al. 1999; Wangemann et al. 2004). SLC26A4 appears to mediate HCO−3 secretion into endolymph and is responsible for the slightly alkaline pH (Fig. 3.7) (Wangemann et al. 2007). SLC26A4 may have a similar role in the vestibular system, where it is expressed in transitional cells (Nakaya et al. 2007). Loss of pendrin leads to the development of enlarged endolymphatic compartments in the cochlea and the vestibular labyrinth and to an acidification of endolymph (Everett et al. 2001). The enlarged endolymphatic compartment in the cochlea requires higher metabolic rates in stria vascularis to sustain higher rates of K+ secretion necessary to maintain K+ homeostasis (Wangemann et al. 2004). Acidification of endolymph coupled with higher metabolic rates causes free radical stress and redox imbalance in stria vascularis. Oxidative stress degenerates stria vascularis and causes the loss of the K+ channel KCNJ10, which leads to deafness via the loss of the normal endocochlear potential (Wangemann et al. 2004, 2007; Singh and Wangemann 2008). Acidification of endolymph

inhibits Ca2+ absorption and elevated Ca2+ concentrations in endolymph inhibit the transduction channel (Wangemann et al. 2007). In addition, progressive degeneration of stria vascularis is associated with an invasion of macrophages into stria vascularis (Jabba et al. 2006).

In the thyroid SLC26A4 is partially responsible for I− transport across the apical membrane of thyroid follicular epithelial cells. Mutations of SLC26A4 appear to limit iodide fixation in the follicular lumen, which may lead to a compensatory enlargement of the thyroid gland (Bidart et al. 2000).

7.3 Jervell–Lange-Nielsen Syndrome

Jervell–Lange-Nielsen syndrome is a rare autosomal recessive disease characterized by profound sensorineural deafness and prolonged QT-intervals of the cardiac action potentials that in response to exercise or emotions can precipitate arrhythmias, syncope and even sudden death in otherwise healthy individuals (Jervell and Lange-Nielsen 1957). Jervell–Lange-Nielsen syndrome is due to severe mutations of the K+ channel -subunit KCNQ1 and/or the -subunit KCNE1 that are required for proper K+ channel function (Neyroud et al. 1997; Schulze-Bahr et al. 1997; Wang et al. 2002).

In the inner ear, the K+ channel KCNQ1/KCNE1 is expressed in the apical membrane of strial marginal cells and vestibular dark cells (Sakagami et al. 1991; Marcus and Shen 1994; Wangemann et al. 1995a). This K+ channel is essential for K+ secretion across the apical membrane of strial marginal cells and vestibular dark cells. Without this channel, K+ secretion fails and endolymphatic spaces in patients suffering from Jervell–Lange-Nielsen syndrome appear to be collapsed (Friedmann et al. 1966). Similarly, mice that lack KCNE1, KCNQ1, or harbor a spontaneous mutation in KCNE1 develop normally endolymphatic spaces until the onset of K+ secretion. The onset of K+ secretion is likely paralleled by the onset of absorptive processes. Failure of K+ secretion in the presence of unimpeded absorptive processes leads to the apparent collapse of endolymphatic spaces in mice as seen in human patients (Vetter et al. 1996; Lee et al. 2000; Letts et al. 2000; Casimiro et al. 2001).

The KCNQ1/KCNE1 K+ channel is not only responsible for K+ secretion and the formation of endolymph in the cochlear and vestibular labyrinth but carries in cardiac myocytes the slowly activating IKs current that plays a major role in the repolarization phase of the cardiac action potential (Varnum et al. 1993; Barhanin et al. 1996; Sanguinetti et al. 1996). Although transcription of KCNQ1 in the heart is independent of KCNE1, it appears that KCNQ1 interacts at the translational or posttranslational level with KCNE1 (Drici et al. 1998). Support for a posttranslational interaction comes from the observation that KCNQ1 in vestibular dark cells of mice lacking KCNE1 failed to concentrate in the apical membrane and appeared to remain in the cytoplasm rather than being trafficked to the apical membrane (Nicolas et al. 2001). Thus, KCNE1 may be necessary for trafficking of KCNQ1 to the apical membrane.