Unlike other types of sensory receptor cells, hair cells do not rely on a cascade of chemical reactions to generate a signal. Photoreceptor cells in the eye, for instance, require a series of intricate interactions with a G protein and a second messenger before their ion channels close, sending a signal to the brain.

This process would be much too slow to deal with sounds. Hair cells have to possess a mechanism that allows their ion channels to open and close more rapidly than those of any other sensory receptor cells.

Therefore hair cells use something very much like a spring that opens their channels when the cilia bend, without the need for a time-consuming chemical exchange.

Corey and Hudspeth first theorized in the early 1980s that such a "gating spring" mechanism existed. They proposed that hair cells had a previously unknown type of ion channel—a channel directly activated by mechanical force. They also developed a biophysical theory to account for the hair cells' rapid response. But their theory didn't tell them where the channels were or what the spring was.

By painstakingly measuring the electrical field around the cilia with an electrode, Hudspeth detected a tiny drop in voltage at the cilia's tips, as if the current were being sucked into a minute whirlpool.

This led him to conclude that the channels through which charged particles move into the cell, changing its electrical potential, were located at the cilia's tips. He then reasoned that the gating springs that opened these channels should be there as well.

The springs themselves were first observed in 1984, in electron microscope images taken by James Pickles and his colleagues in England. Called tip links, these minute filaments join each stereocilium to its tallest neighbor.

Pickles pointed out that the geometry of the cilia bundle would cause the bundle to stretch the links when it was deflected in one direction and relax them when it was moved in the other. If the tip links were the hypothetical gating springs, it would explain everything.

"This was a completely new kind of mechanism, unlike anything ever observed before," says Corey, who provided compelling evidence that the tip links pull on the channels. By "cutting" the tip links with a chemical, Corey could stop the cell's response cold. "Within less than a second, as the tip links became unstable, the whole mechanical sensitivity of the cell was destroyed," Corey observed.

Recently, both he and Hudspeth have independently investigated another property of hair cells: their ability to adapt to being deflected.

At first, when a hair cell bundle is deflected, the ion channels open. But if the bundle remains deflected for a tenth of a second, the channels close spontaneously. It appears from electron microscope images and physiological evidence that the channels close when the tip links relax. This is related to the activity of the tip links' attachment points, which can move up and down along the cilia to fine-tune the tension on the channels. When the attachment points move down, the tip links are relaxed and the ion channels close.

While the researchers are still trying to figure out what enables the attachment points to move, they strongly suspect that myosin plays a role. Myosin is the protein that gives muscle cells their ability to contract. Both the Hudspeth and Corey labs have now cloned and sequenced the gene for a particular type of myosin in hair cells, and both have found that this myosin is located at the tips of the stereocilia, near the ion channels. A cluster of such molecules in each stereocilium could provide the force to move the attachment point up or down.

Slight movements of the attachment points allow the hair cell to set just the right amount of tension on each channel so it is maximally sensitive. They also permit the cell to avoid being overloaded when it is barraged by sound.

A second type of hair cell in the highly specialized cochlea of mammals may enable us to distinguish the quietest sounds. These outer hair cells, which are shaped like tiny hot dogs, look distinctly different from inner hair cells.

The outer hair cells have a peculiar ability to become shorter or longer in microseconds when stimulated, doing so with a flamboyant, bouncy, up-and-down motion not found in any other cell type. They outnumber inner hair cells 3 to 1. Yet the 4,000 inner hair cells are connected to most of the auditory nerve fibers leading to the brain and are clearly the main transmitters of sound.

The precise function of the outer hair cells is still unclear. Auditory researchers speculate that these cells may serve as an amplification mechanism for tuning up low-frequency sound waves, possibly by accelerating the motion of the basilar membrane.

Hudspeth is also intrigued by the possibility that outer hair cells may be responsible for something that has puzzled researchers for years: the fact that our ears not only receive sounds, but emit them as well.

When sensitive microphones are placed in the ear and a tone is played, a faint echo can be detected resonating back out again. Such otoacoustic emissions are considered normal; in fact, their presence in screening exams of newborn babies is thought to be indicative of healthy hearing. However, in certain cases, otoacoustic emissions can be spontaneous and so intense that they are audible without the aid of special equipment.

"In some people, you can actually hear them. The loudest ones ever recorded were in a dog in Minnesota, whose owner noticed the sound coming out of the animal's ear and took the dog to a specialist, who did recordings and analysis," says Hudspeth.

"What may be happening is that the amplification system driven by the movements of outer hair cells is generating feedback, like a public address system that's tuned up too high," he speculates, adding that such otoacoustic emissions gone awry may account for certain unusual forms of tinnitus, or ringing in the ear.

Hudspeth and Corey's research is providing such a detailed picture of the hair cell that it is now possible to start identifying the individual proteins making up the tip links, ion channels, and motor mechanisms involved, as well as the genes that produce them. Malfunctions in those genes, resulting in defects in these important structures, may be the cause of inherited forms of deafness.

For more information on James Hudspeth and the study of hearing, see 1997 Holiday Lectures.

— Jeff Goldberg

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The movement of a hair cell's cilia bundle (top left) opens ion channels...

	On the Trail of Deafness Genes

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