Long-sought key to hearing may be found in protein discovery

October 13, 2004

BOSTON, MA--Researchers at Harvard Medical School and their colleagues report in the October 13 Nature advanced on-line edition that they have identified a protein deep in the inner ear that they believe translates sound into the nerve impulses used by the brain.

"People have been looking for this protein for a decade," says David Corey, HMS professor of neurobiology and an investigator of the Howard Hughes Medical Institute. Other protein candidates have been nominated, but this is "the strongest evidence yet that this protein is the hair-cell transduction channel," says Corey, lead author of the paper.

The discovery could help scientists investigate normal hearing and inherited forms of deafness, which typically involve other protein pieces of the same acoustic apparatus, says Corey, also co-director of the HMS Center for Hereditary Deafness.

"This is the most important molecule in the ear," said Peter Gillespie, a neurobiologist at Oregon Health & Science University who recently has helped identify important parts connecting to either side of the channel. "This channel is the jewel everyone would like to find. Identifying it is getting at the real kernel of how the inner ear works."

The protein, TRPA1 (pronounced TRIP-AY-ONE), is located at the tips of specialized cilia on hair cells of the inner ear. Scientists believe the protein forms pores that open and close in sync with sound waves, allowing ions to flow into the cells and to transform the vibrations into electric signals. The same protein channel also may help people distinguish between tones of different frequencies.

Sound travels through the auditory system like a message relayed through the jungle from drum to drum. Snippets of conversation or the roar of a leaf blower are collected by the fleshy outer part of the ear and funneled inside where a delicate percussion section vibrates, taps and shivers.

The key elements in converting sound into nerve impulses are the bundles of cilia that protrude from the tops of hair cells and give them their name. Inside the cochlea, the stiff cilia bend at their bases when the pulsing sound waves push against them thousands of times a second. Small protein strings called tip links connect the tip of each cilium with its taller neighbor. (Six months ago, other researchers discovered the molecular identity of the tip links.) With each vibration, the bending cilia pull on the links connecting them, yanking open the channels to allow ions to flood into the cilia. The resulting voltage change activates the conversion of sound to a nerve signal. Then, the cilia bend back and ion channels snap shut.

"Hair cells convert a mechanical stimulus into an electrical signal with molecular, strings, springs and levers," Corey says. "It's cell biology, but it's wonderfully mechanical as well."

In their paper, Corey and his colleagues present evidence that the mysterious ion channel is actually TRPA1. The TRP proteins are a trendy new family of ion channels involved in sensory perception. Different TRP proteins help insects see and hear, mammals taste and sense heat and pheromones. A small clan known as TRPN help fruit flies sense touch and fish hear.

At the beginning of their study, Corey and his colleagues systematically evaluated all of the several dozen mouse TRP channels with RNA probes to locate the ones expressed by hair cells of the mouse cochlea. TRPA1 looked most promising. Using antibodies to TRPA1, the team found that the channels were located at the tips of hair cell cilia.

As attractive as the protein appeared, it had to pass several other rigorous tests made possible by scientific advances in the last several years. In zebrafish, the researchers blocked expression of the TRPA1 protein and found their hair cells did not generate electrical signals in response to vibration. In a related test, these hair cells showed none of the telltale glow when exposed to a fluorescent dye that usually pours in through working transduction ion channels.

In the third set of experiments, collaborators at the University of Virginia School of Medicine genetically blocked the TRPA1 channel in hair cells of embryonic mice, using siRNAs carried in with adenoviruses, and measured the response. They recorded barely any electrical activity in the hair cells with blocked TRPA1. Likewise, the hair cells did not take up the fluorescent dye. Although the discovery needs confirmation by other methods, TRPA1 is the best candidate for the hair-cell transduction channel.

What are the implications for hearing and deafness? "Other protein components of the transduction apparatus cause inherited deafness and blindness when mutated," Corey says. "Although there is no evidence for it at the moment, the same may be true for TRPA1. Having the transduction channel will accelerate a search for the remaining protein pieces, and these in turn may be causes of inherited deafness."
Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Hospital, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.

EDITOR'S NOTE: On Wednesday morning, a video clip interview of the investigator and animation of the research will be available at www.hms.harvard.edu/news/corey_TRP.mov Images are available now upon request.

Harvard Medical School

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