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Hearing sense organs, though somewhat variable among species in cellular organization and disposition, all utilize mechanically sensitive receptor hair cells to accomplish the transduction of acoustic stimuli into electrical activity which informs the brain. The frequency components of complex stimuli are resolved and spatially encoded by the peripheral organ; this tonotopic information is preserved and addressed through several relay nuclei in the pathway to the auditory cortex. Frequency analysis is performed by the peripheral organ using mechanisms which are either extrinsic, or intrinsic, to the hair cell. It is generally agreed that the basilar membrane, upon which hair cells sit, is the major component of the frequency analyser in the mammalian organ of Corti. Sounds of different frequencies maximally displace the basilar membrane at different locations, resulting in differential stimulation among the population of hair cells. The mechanically tuned basilar membrane, boosted by feedback from the outer hair cells, thereby filters the stimulus, so that a given hair cell is exposed to only a narrow range of frequencies. In a number of lower vertebrates, however, the basilar membrane is poorly or not at all tuned and frequency analysis is predominantly the task of the hair cells themselves.
Much of what is known about intrinsic hair cell tuning and its role in the tonotopic organization of lower vertebrate auditory receptors derives from an elegant series of studies of the turtle cochlea by Fettiplace and his colleagues. Turtle auditory hair cells, whether stimulated acoustically or by extrinsic current injections, exhibit similar damped oscillations in membrane potential, the frequencies of which vary systematically as a function of hair cell location along the receptor epithelium (Crawford & Fettiplace, 1981). The turtle's auditory range is largely spanned by the frequency range of these intrinsic hair cell resonances. Since a given hair cell's largest receptor potential and consequent neurotransmitter release are evoked by stimulus frequencies corresponding to that cell's resonant frequency, frequency analysis in this receptor is carried out by a population of hair cells each of whose unique properties predetermine the stimulus frequency at which it will be stimulated maximally.
What are the determinants of hair cell resonant frequency and how might the variability among hair cells be generated? Electrical resonance results from the kinetic interplay between basolateral voltage-gated calcium channels and nearby large-conductance calcium-activated potassium (BK) channels, as modelled by Hudspeth & Lewis (1988) for the frog sacculus and Wu et al. (1995) for the turtle cochlea. In principle, therefore, a hair cell's resonant frequency might be determined by one, or a combination, of the following: calcium channel number or kinetics, local calcium buffering kinetics, or BK channel number or kinetics. Using both whole-cell and single-channel recordings to study turtle cochlear hair cells tuned to a range of frequencies, Fettiplace and colleagues showed that BK channel properties were most important; cells tuned to higher frequencies had more BK channels and these channels exhibited faster kinetics (reviewed in Fettiplace & Fuchs, 1999). In particular, the macroscopic current relaxation time constants were found to vary over a range sufficient to account for nearly the full frequency range of hearing in the turtle, and this kinetic variability was intrinsic to the BK channels. The remarkable implication of these results is the existence of a family of hair cell BK channels with varying kinetic properties, whose members are selectively expressed in hair cells according to the cells' positions along the tonotopic axis of the epithelium. Recent demonstrations of the presence in chick cochlear hair cells of a large number of alternatively spliced transcripts derived from slo, a gene which encodes the 
-subunit of BK-type channels, suggested a potential mechanism for the generation of this family of BK isoforms (Navaratnam et al. 1997; Rosenblatt et al. 1997; Ramanathan et al. 1999).
In a paper in this issue of The The Journal of Physiology, Jones et al. (1999) report the detailed functional characterization of six cloned naturally occurring turtle cochlear hair cell Slo channel -subunit isoforms, demonstrating therein a range of channel properties which comes close to accounting for the range of BK channel properties previously measured in native turtle hair cells. The six channel -subunit isoforms studied by these investigators, related to each other by differential splicing at two sites, exhibited clear differences both in apparent calcium sensitivity and in relaxation kinetics. Co-expression in the heterologous system of two different but related modulatory 
-subunits (one bovine and one avian) with each of the -subunits slowed all of their current relaxations and increased all of their apparent calcium sensitivities, while preserving their rank orders in these two properties. Based on the calcium sensitivities and relaxation time constants determined for the various cloned channel species, Jones et al. (1999) were able to devise a scheme of differential expression of channel isoforms which does rather well in matching the data from native hair cells distributed over the tonotopic axis of the turtle cochlea. An important assumption in their scheme is that the -subunit is expressed in only the low-frequency portion of the epithelium in order to bring the calcium sensitivities of the appropriate -subunits into the range of sensitivities of the native hair cell channels. While there has not yet been molecular confirmation of -subunit expression in the turtle cochlea, Ramanathan et al. (1999) have shown that a -subunit is expressed in the chick cochlea, and that its expression is greater in the low-frequency portion of the epithelium. Finally, limited molecular data obtained by Jones et al. (1999) on the distribution across the turtle cochlea of several -isoforms is consistent with the proposed scheme.
In summary, the report by Jones et al. (1999) provides strong evidence that differential splicing along the tonotopic axis of calcium-activated potassium channel transcripts plays a major role in the intrinsic tuning of receptor hair cells. This remarkable mechanism may not be the only one; other mechanisms intrinsic to the hair cell are also likely to play a role (see Fettiplace & Fuchs, 1999). The mechanisms through which the differential processing of BK channel transcripts is regulated in such a systematic fashion across the receptor epithelium promise to be fertile grounds for further research.
| Crawford, A. C. & Fettiplace, R. (1981). The Journal of Physiology 312, 377-412 | [Medline] |
| Fettiplace, R. & Fuchs, P. A. (1999). Annual Review of Physiology 61, 809-834 | [Abstract/Full Text] |
| Hudspeth, A. J. & Lewis, R. S. (1988). The Journal of Physiology 400, 275-297 | [Abstract] |
| Jones, E. M. C., Gray-Keller, M. & Fettiplace, R. (1999). The Journal of Physiology 518, 653-665. | [Abstract/Full Text] |
| Navaratnam, D. S., Bell, T. J., Tu, T. D., Cohen, E. L. & Oberholtzer, J. C. (1997). Neuron 19, 1077-1085 | [Medline] |
| Ramanathan, K., Michael, T. H., Jiang, G.-J., Hiel, H. & Fuchs, P. A. (1999). Science 283, 215-217 | [Abstract/Full Text] |
| Rosenblatt, K. P., Sun, Z.-P., Heller, S. & Hudspeth, A. J. (1997). Neuron 19, 1061-1075 | [Medline] |
| Wu, Y.-C., Art, J. J., Goodman, M. B. & Fettiplace, R. (1995). Progress in Biophysics and Molecular Biology 63, 131-158. | [Medline] |
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