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The Role of Potassium Recirculation in Cochlear Amplification

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The Role of Potassium Recirculation in Cochlear Amplification The role of potassium recirculation in cochlear amplification Pavel Mistrika and Jonathan Ashmorea,b aUCL Ear Institute and bDepartment of Neuroscience, Purpose of review Physiology and Pharmacology, UCL, London, UK Normal cochlear function depends on maintaining the correct ionic environment for the Correspondence to Jonathan Ashmore, Department of sensory hair cells. Here we review recent literature on the cellular distribution of Neuroscience, Physiology and Pharmacology, UCL, Gower Street, London WC1E 6BT, UK potassium transport-related molecules in the cochlea. Tel: +44 20 7679 8937; fax: +44 20 7679 8990; Recent findings e-mail: [email protected] Transgenic animal models have identified novel molecules essential for normal hearing Current Opinion in Otolaryngology & Head and and support the idea that potassium is recycled in the cochlea. The findings indicate that Neck Surgery 2009, 17:394–399 extracellular potassium released by outer hair cells into the space of Nuel is taken up by supporting cells, that the gap junction system in the organ of Corti is involved in potassium handling in the cochlea, that the gap junction system in stria vascularis is essential for the generation of the endocochlear potential, and that computational models can assist in the interpretation of the systems biology of hearing and integrate the molecular, electrical, and mechanical networks of the cochlear partition. Such models suggest that outer hair cell electromotility can amplify over a much broader frequency range than expected from isolated cell studies. Summary These new findings clarify the role of endolymphatic potassium in normal cochlear function. They also help current understanding of the mechanisms of certain forms of hereditary hearing loss. Keywords cochlea, cochlear amplifier, computational modeling, endolymph, gap junctions, hair cells, potassium, stria vascularis, transporters Curr Opin Otolaryngol Head Neck Surg 17:394–399 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1068-9508 Energy demands are made on stria vascularis instead. An Introduction additional explanation may be that the great diversity of Potassium (Kþ) is the major ion of the inner ear endo- potassium channel proteins means that hair cells can lymph and fills the entire scala media of the cochlea. The employ multiple strategies to extrude Kþ.Kþ channels rest of the cochlea contains perilymph, a conventional are certainly used in ionic pathways in hair cells [2,3]. extracellular fluid. Why does scala media contain high However, when Kþ does enter the cell, the resulting Kþ? With low levels of sodium and calcium, endolymph depolarization leads to force generation by the outer hair resembles intracellular medium. Its composition is main- cells (OHCs; reviewed in [4–6]) and activates transmitter tained by the correct operation of the stria vascularis release form inner hair cells onto the afferent nerve. We along the full length of the cochlea. It has long been a shall concentrate here on the Kþ flow and OHC mech- puzzle why scala media contains this high Kþ solution. In anisms. this article, we show that the cochlear design takes advantage of many different possible Kþ permeant path- Cochlear amplification is shorthand for the processes that ways in order to achieve its sensitivity to sound. inject power into the partition and increase auditory sensitivity by a factor of more than 100Â (40 dB). The mechanism can be traced to the correct operation of the Hair cells and cochlear amplification OHCs and, in turn, to the insertion into the OHC The mechanotransducing surfaces of hair cells face the basolateral membrane of multiple copies of a protein same high Kþ composition fluids in both vertebrate and, SLC26A5 (prestin). There are arguments that these probably, in invertebrate systems too [1]. During sound forces could originate from the stereociliary bundle itself stimulation, Kþ becomes the charge carrier entering [6–8], but such mechanisms depend primarily on the through the transducer channels. A partial explanation entry of calcium, rather than Kþ, through the transducer for a high endolymphatic Kþ is that transduction does not channels. Prestin, acting as a voltage-gated mechano- thereby place a high metabolic load on the hair cells. enzyme, depends on the potentials across the OHC 1068-9508 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOO.0b013e328330366f Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Potassium recycling in cochlear amplification Mistrik and Ashmore 395 basolateral membrane. As a result, both intracellular and The permeabilities of connexin hemichannels in normal extracellular potentials determine the operation of the physiological conditions are unclear. amplifier. Both of these potentials depend on the distri- bution of Kþ within the organ of Corti. Despite uncertainty about the exact Kþ pathway, the candidates for its transport into stria vascularis are poorly Much of what we understand of the amplification process understood. The presence of Kþ/Naþ ATPase activity and is informed by computer models of the cochlea. Despite aKþ/Naþ/2ClÀ co-transporter in type II fibrocytes of the many decades of effort, there is no complete agreement spiral ligament suggests that Kþ is actively transported. about the ‘best’ model, as many of the processes are Immunolocalization of other gap junctional proteins nonlinear. There is agreement that amplification depends (Cx30) between II fibrocytes with basal and intermediate on feedback operating close to instability regimes. In cells of stria vascularis [24] suggests that Kþ diffusion these cases, the precise parameters and regulation of the occurs through the connective tissue gap junction system parameters become critical. Kþ recirculation plays a into stria vascularis. The stria vascularis itself forms a significant part in this homeostasis. system of electrically isolated compartments characterized by tight junctions forming barrier between the compart- ments [25] and two Kþ-diffusion potentials [26]. In this R Molecular recycling pathways for K in the system, the absence of the underlying transport proteins cochlea can be responsible for a hereditary hearing loss [27]. The Several crucial potassium transport-related molecules absence of Cx30 in the stria vascularis is also reported to have been found in very specific cochlear compartments lead to hearing losses [28]. In this latter case, it has been [9,10]. The compartments include hair cells and sup- proposed that disruption of this gap junction protein leads porting cells in the organ of Corti, type II fibrocytes in the to the endothelial barrier of the capillaries supplying the spiral ligament, and the intermediate and marginal cells stria vascularis to becoming leaky; the resulting intrastrial of stria vascularis. This expression pattern strongly sup- electric shunt would then be sufficient to reduce any ports the idea that potassium is moved between cochlear epithelial potentials significantly during development. compartments during sound transduction (reviewed in [11,12]). The endolymphatic compartment is held at a positive potential of at least þ80 mV. This endocochlear potential The recycling hypothesis proposes that Kþ enters the is generated by a large Kþ-diffusion potential generated OHCs and IHCs through the apical mechanotransducer across the apical membrane of intermediate cells of the channels. Intracellular Kþ buildup is prevented by the stria vascularis (reviewed in [12]). The major molecular activation of Kþ conductances (KCNQ4 [2], SK, and BK component responsible is inward rectifier channel [13] channels) localized around the OHC basal pole KCNJ10 (Kir4.1) [29,30]. The low Kþ levels (5 mmol/ [2,14]. The subsequent pathway for Kþ ions is less clear. l) in the intrastrial space between the marginal and inter- In one classical scenario, Kþ ions diffuse extracellularly mediate cells is maintained by the action of a Kþ/Naþ through the tunnel of Corti to reach perilymph [15]. The ATPase, a Kþ/Naþ/2ClÀ co-transporter (SLC12A2) and a existence of this low-impedance pathway is supported by ClÀ return path at the base of the marginal cells [31]. classical measurements of current loops in the cochlea Finally, Kþ permeates into scala media through a further in vivo [16] and from current injection experiments [17]. potassium channel complex, KCNQ1/KCNE1 in the api- cal membrane of marginal cells [32]. An alternative proposal is that Kþ ions are taken up by neighboring Deiters’ cells. Mice lacking the K-Cl co- The resulting 150 mmol/l Kþ concentration in scala transporters Kcc4 or Kcc3, both normally expressed in media is a necessary (but not sufficient) condition for Deiters’ cells, are deaf [18,19]. From the Deiters’ cells, the þ80 mV of endocochlear potential. Indeed, during Kþ ions pass through the epithelial tissue gap junction development, high Kþ in scala media precedes the estab- system coupling supporting cells in the organ of Corti lishment of endocochlear potential by 2–3 days [33]. [20]. This gap junction system is implicated by the Even when hearing matures, normally at day P14 in extensive evidence from human GJB gene mutations the mouse, the endocochlear potential still has not and in mouse models in which targeted ablation of con- reached its final adult value of nearly 100 mV. The nexin 26 (Cx26) in the organ of Corti leads to deafness difference in the timing may be due to experimental [21]. The gap junction system represents a potentially techniques, but it seems likely that high values of endo- high-impedance pathway between cells’ in contrast to the cochlear potential require full maturation of tight elec- low-impedance extracellular pathway through the tunnel trical junctions and maturity of the pumps in the stria of Corti. It is also not known how Kþ ions are released vascularis itself. The precise estimate of the necessary from the gap junction system into perilymph, although balance can benefit from relatively simple computer connexin hemichannels may form one route [22,23]. models of stria vascularis [34]. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 396 Hearing science þ R [35].
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