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• W2061650897 abstract "Hair cells, the sensory receptors of the inner ear, respond to a constant mechanical stimulus with a transducer current that decreases gradually with time: adaptation (Eatock et al. 1987). The hair bundles on the apical surface of the cells are composed of tens to hundreds of stereocilia connected by tip links which are the prime candidates for gating a comparable number of mechanosensitive non-selective cation channels. In the absence of a stimulus about 10 % of these transducer channels are open and the channels are at their most sensitive near this resting position. The most important function of transducer current adaptation is probably to keep the transducer channels in the hair bundles operating within their most sensitive range, independent of static displacements or forces that may be imposed on them. Adaptation is controlled by Ca2+ ions which flow down their electrochemical gradient through the transducer channels and reduce their opening probability, probably by reducing the effectiveness of myosin motors that keep the tip links under a certain resting tension (Hudspeth & Gillespie, 1994). Paradoxically, while Ca2+ plays such a crucial role in mediating adaptation, there is hardly any free Ca2+ (30-65 μM) in the endolymph, the unusual K+-rich extracellular solution at the apical surface of the hair cells. To make matters worse, adaptation disappears when isolated hair cells are perfused with solutions containing realistic endolymphatic Ca2+ concentrations, instead of the concentrations greater than 1 mM commonly employed experimentally (Crawford et al. 1991). So, where does the Ca2+ come from to drive adaptation in vivo? It has to date not even been possible to demonstrate this type of adaptation convincingly in vivo, for lack of direct measurements of transducer currents in living animals. Two recent papers in TheThe Journal of Physiology, one of them in this issue, provide some solutions to the puzzle. The first step taken by Ricci & Fettiplace (1997) was to develop an intact preparation of the cochlear epithelium isolated from the turtle Trachemys scripta elegans. Retention of the tight junctions within the epithelium allowed the apical and basolateral membranes of the hair cells to be perfused independently with different solutions. The transducer currents were larger than those previously recorded from isolated turtle hair cells, presumably reflecting less damage to the hair bundles in the intact epithelium. Moreover, there was a gradient in the transducer currents along the tonotopically arranged epithelium: high-frequency cells had larger currents and faster adaptation than cells from the low-frequency end. When the apical surfaces were perfused with a solution containing 50 μM Ca2+, adaptation was abolished in some cells as reported before, but in others the extent of adaptation was merely reduced and its time course slowed. High-frequency cells with large transducer currents were most resistant in this respect. All these experiments were done using whole-cell patch clamp, in which the composition of the intracellular solution is largely determined by that inside the patch pipette. The concentration of the Ca2+ buffer BAPTA in the pipette was found to affect the extent and rate of adaptation strongly: low concentrations of buffer made adaptation more complete and reduced its time constant. These results show that transducer current adaptation should indeed be possible in vivo, provided that the endogenous Ca2+ buffering capacity in the hair bundles is less than that commonly used in patch pipettes: equivalent to at most 1 mM BAPTA for high-frequency cells and 0.1 mM for low-frequency cells. Adaptation is thus possible despite the low Ca2+ concentration in the endolymph, but how can this be explained?Ricci & Fettiplace (1998) used an ingenious method that combines fluorescence and current measurements (Schneggenburger et al. 1993) to deduce the fractional contribution of Ca2+ current to the total current through non-selective cation channels. They found that with Na+ as the main extracellular cation, the fractional Ca2+ current is about 60 % in 2.8 mM external Ca2+, and still as much as 15 % in 50 μM Ca2+. If fractional current were simply proportional to concentration, one would expect it to reduce to 1 %! Replacing Na+ with K+ as the main cation to mimic endolymph, the fractional Ca2+ current is even larger, about 20 %. Ca2+ also acts as a partial blocker of the transducer current, with the effect that the total transducer current is twice as large in artificial endolymph containing 50 μM Ca2+ than it is in Na+-based extracellular solution containing 2.8 mM Ca2+. For the same stimulus, the absolute Ca2+ entry into the bundle surrounded by endolymph is therefore expected to be approximately two-thirds of that in normal extracellular solution. These surprising findings can be explained if the transducer channel is a multi-ion pore in which the different cations interact as they pass through the channel. The low Ca2+ concentration in the endolymph maximizes the transducer current (and thus the sensitivity of the hair cells), while the nature of the ionic interaction between K+ and Ca2+ in the pore still allows sufficient Ca2+ entry for adaptation. These studies demonstrate that transducer current adaptation can occur at realistic endolymphatic Ca2+ concentrations, and give an insight into why this is possible. Several questions remain. For example, what is the molecular nature of the endogenous Ca2+ buffer in the hair bundles and does its concentration vary along the tonotopic axis? How is it exactly that cells with larger maximum transducer currents exhibit faster and more complete adaptation, given that the current per transducer channel is invariant? What are the time constants and extent of adaptation along the mammalian cochlea? The sophisticated in vitro approach used in these experiments, in which hair cells are not isolated but kept as much as possible in their natural environment, promises to answer such questions in the future." @default.
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• W2061650897 date "1998-01-01" @default.
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• W2061650897 title "The paradox of hair cell adaptation" @default.
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• W2061650897 doi "https://doi.org/10.1111/j.1469-7793.1998.001bx.x" @default.
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