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Hey presto! Electrophysiological characterisation of prestin, a motor protein from outer hair cells, transfected into kidney cells

Michael G. Evans and Corné J. Kros *

The mammalian cochlea is a frequency analyser, informing the brain of the component frequencies in a complex sound via tonotopically organised sensory nerve fibres. The hair cells, organised into two distinct morphological types, are located between the tectorial membrane and the mechanically tuned basilar membrane. The inner hair cells, arranged in a single row, receive most of the afferent innervation, and are thus primarily responsible for transmitting auditory information to the brain. The outer hair cells, in three rows strategically arranged on the basilar membrane, receive mainly efferent innervation, and are known to play a vital role in locally amplifying the travelling wave as it passes along the basilar membrane. As far as we know the outer hair cells are unique: they have an ultra fast motility, gated by the cell's own receptor potential, which allows forces to be 'fed back' into the travelling wave, giving a considerable boost to its amplitude and tuning. The motility arises from voltage-dependent conformational changes in a motor molecule that is densely packed, at an estimated 7500 motors per square micrometre, into the outer hair cell's lateral cell membrane. These conformational changes alter the cell's membrane surface area, which when constrained by the submembrane cortical lattice produce changes in cell length (Kalinec et al. 1992).

Recent research has now shed light on the molecular components behind the outer hair cell's motor. While the cochlea is notoriously stingy in giving up its molecular secrets to molecular biological techniques, differences between the two hair cell types were harnessed to track down the gene for the outer hair cell's motor protein (Zheng et al. 2000). The protein, named prestin, has some sequence homology with sulphate transporters. When transfected into a kidney cell line, it conferred fast motility on the partially constrained and unsuspecting kidney cells. In common with outer hair cells, motility was accompanied by a charge movement producing a non-linear cell capacitance. One peculiarity of the non-linear capacitance, which exhibits a shallow bell-shaped voltage dependence with a peak capacitance at about -30 mV, is that the peak appears to shift to more depolarised potentials if the cell is clamped to more negative potentials beforehand (Santos-Sacchi et al. 1998). Thus the motor protein exhibits simple memory, in molecular form. Furthermore, the motor molecule's behaviour is influenced by membrane tension, with positive intracellular pressures producing a positive shift in peak capacitance. In this issue of The Journal of Physiology, Santos-Sacchi et al. (2001) report similar behaviour in kidney cells transfected with prestin. Thus prestin does indeed appear to be the outer hair cell's molecular motor.

The story does not stop there, however. A comparison between outer hair cells and prestin-expressing kidney cells shows sizeable quantitative differences in the voltage corresponding to the peak capacitance, and the extent of the shift in this voltage with negative pre-pulses and intracellular pressure. In the prestin-expressing kidney cells the peak-capacitance voltage is more negative and the shifts are smaller. It is therefore possible, even probable, that other molecules, presumably proteins, are necessary to couple prestin to the cortical lattice, thereby allowing it to function effectively in situ. The leading candidate for inclusion in such a motor complex is the sugar transporter GLUT-5, also implicated in outer hair cell electromotility (Géléoc et al. 1999), and also localised to the lateral membrane of outer hair cells (Belyantseva et al. 2000). The expression of GLUT-5 during cochlear development in rats, however, lags behind that of prestin and the onset of outer hair cell motility by about 6 days, indicating that it is less intrinsic than prestin to electromotility. One possibility is that GLUT-5 might simply be there to provide fuel for energy-requiring processes beneath the cell membrane that regulate motility. The next step would be to co-express GLUT-5 with prestin in kidney cells to see if this produces a more normal operating range for the motor. The motor's operating range is already known to depend on the developmental age of the cell (Oliver & Fakler, 1999) and on the level of protein phosphorylation (Frolenkov et al. 2000).

Whatever the final structure and identity of the outer hair cell motor, prestin must be a fundamental component. But over and above this, the elegant use of the techniques used to track down and harness prestin is bound to provide considerable impetus towards a long sought-after goal in the physiology of hearing: understanding the molecular basis of the cochlear amplifier.

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BELYANTSEVA I. A., ADLER, H. J., CURI, R., FROLENKOV, G. I. & KACHAR, B. (2000). Journal of Neuroscience 20, RC116 (1-5).	[Medline]
FROLENKOV G. I., MAMMANO, F., BELYANTSEVA, I. A., COLING, D. & KACHAR, B. (2000). Journal of Neuroscience 20, 5940-5948.	[Abstract/Full Text]
GÉLÉOC G. S. G., CASALOTTI, S. O., FORGE, A. & ASHMORE, J. F. (1999). Nature Neuroscience 2, 713-719.	[Medline]
KALINEC F., HOLLEY, M. C., IWASA, K. H., LIM, D. J. & KACHAR, B. (1992). Proceedings of the National Academy of Sciences of the USA 89, 8671-8675.	[Abstract]
OLIVER D. & FAKLER, B. (1999). Journal of Physiology 519, 791-800.,	[Abstract/Full Text]
SANTOS-SACCHI J., KAKEHATA, S. & TAKAHASHI, S. (1998). Journal of Physiology 510, 225-235.	[Abstract/Full Text]
SANTOS-SACCHI J., SHEN, W., ZHENG, J. & DALLOS, P. (2001). Journal of Physiology 531, 661-666.	[Abstract/Full Text]
ZHENG J., SHEN, W., HE, D. Z., LONG, K. B., MADISON, L. D. & DALLOS, P. (2000). Nature 405, 149-155.	[Medline]

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